Imidazo[4,5-c]quinolin-2-one Compounds and Their Use in Treating Cancer

ABSTRACT

The specification generally relates to compounds of Formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             and pharmaceutically acceptable salts thereof, where Q, R 1 , R 2 , R 3 , R 4  and R 5  have any of the meanings defined herein. The specification also relates to the use of such compounds and salts thereof to treat or prevent ATM kinase mediated disease, including cancer. The specification further relates to crystalline forms of compounds of imidazo[4,5-c]quinolin-2-one compounds and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds and salts; kits comprising such compounds and salts; methods of manufacture of such compounds and salts; intermediates useful in the manufacture of such compounds and salts; and to methods of treating ATM kinase mediated disease, including cancer, using such compounds and salts.

FIELD OF INVENTION

The specification generally relates to substitutedimidazo[4,5-c]quinolin-2-one compounds and pharmaceutically acceptablesalts thereof. These compounds and their pharmaceutically acceptablesalts selectively modulate ataxia telangiectasia mutated (“ATM”) kinase,and the specification therefore also relates to the use of suchcompounds and salts thereof to treat or prevent ATM kinase mediateddisease, including cancer. The specification further relates tocrystalline forms of compounds of substitutedimidazo[4,5-c]quinolin-2-one compounds and pharmaceutically acceptablesalts thereof; pharmaceutical compositions comprising such compounds andsalts; kits comprising such compounds and salts; methods of manufactureof such compounds and salts; intermediates useful in the manufacture ofsuch compounds and salts; and to methods of treating ATM kinase mediateddisease, including cancer, using such compounds and salts.

BACKGROUND

ATM kinase is a serine threonine kinase originally identified as theproduct of the gene mutated in ataxia telangiectasia. Ataxiatelangiectasia is located on human chromosome 11q22-23 and codes for alarge protein of about 350 kDa, which is characterized by the presenceof a phosphatidylinositol (“PI”) 3-kinase-like serine/threonine kinasedomain flanked by FRAP-ATM-TRRAP and FATC domains which modulate ATMkinase activity and function. ATM kinase has been identified as a majorplayer of the DNA damage response elicited by double strand breaks. Itprimarily functions in S/G2/M cell cycle transitions and at collapsedreplication forks to initiate cell cycle checkpoints, chromatinmodification, HR repair and pro-survival signalling cascades in order tomaintain cell integrity after DNA damage (Lavin, 2008).

ATM kinase signalling can be broadly divided into two categories: acanonical pathway, which signals together with the Mre11-Rad50-NBS1complex from double strand breaks and activates the DNA damagecheckpoint, and several non-canonical modes of activation, which areactivated by other forms of cellular stress (Cremona et al., 2013).

ATM kinase is rapidly and robustly activated in response to doublestrand breaks and is reportedly able to phosphorylate in excess of 800substrates (Matsuoka et al., 2007), coordinating multiple stressresponse pathways (Kurz and Lees Miller, 2004). ATM kinase is presentpredominantly in the nucleus of the cell in an inactive homodimeric formbut autophosphorylates itself on Ser1981 upon sensing a DNA doublestrand break (canonical pathway), leading to dissociation to a monomerwith full kinase activity (Bakkenist et al., 2003). This is a criticalactivation event, and ATM phospho-Ser1981 is therefore both a directpharmacodynamic and patient selection biomarker for tumour pathwaydependency.

ATM kinase responds to direct double strand breaks caused by commonanti-cancer treatments such as ionising radiation and topoisomerase-IIinhibitors (doxorubicin, etoposide) but also to topoisomerase-Iinhibitors (for example irinotecan and topotecan) via single strandbreak to double strand break conversion during replication. ATM kinaseinhibition can potentiate the activity of any these agents, and as aresult ATM kinase inhibitors are expected to be of use in the treatmentof cancer, for example as rational combination partners for existingtherapies.

CN102372711A reports certain imidazo[4,5-c]quinolin-2-one compoundswhich are mentioned to be dual inhibitors of PI 3-kinase a and mammaliantarget of rapamycin (“mTOR”) kinase. Among the compounds reported inCN102372711A are the following:

Certain Compounds Reported in CN102372711A

CN102399218A reports certain imidazo[4,5-c]quinolin-2-one compoundswhich are mentioned to be PI 3-kinase a inhibitors. Among the compoundsreported in CN102399218A are the following:

Certain Compounds Reported in CN102399218A

While the compounds or CN102372711A and CN102399218A are reported topossess activity against PI 3-kinase a and in some cases mTOR kinase,there remains a need to develop new compounds that are more effectiveagainst different kinase enzymes, such as ATM kinase. There furtherexists a need for new compounds which act against certain kinaseenzymes, like ATM kinase, in a highly selective fashion (i.e. bymodulating ATM more effectively than other biological targets).

As demonstrated elsewhere in the specification (for example in the cellbased assays described in the experimental section), the compounds ofthe present specification generally possess very potent ATM kinaseinhibitory activity, but much less potent activity against othertyrosine kinase enzymes, such as PI 3-kinase a, mTOR kinase and ataxiatelangiectasia and Rad3-related protein (“ATR”) kinase. As such, thecompounds of the present specification not only inhibit ATM kinase, butcan be considered to be highly selective inhibitors of ATM kinase.

As a result of their highly selective nature, the compounds of thepresent specification are expected to be particularly useful in thetreatment of diseases in which ATM kinase is implicated (for example, inthe treatment of cancer), but where it is desirable to minimiseoff-target effects or toxicity that might arise due to the inhibition ofother tyrosine kinase enzymes, such as class PI 3-kinase a, mTOR kinaseand ATR kinase.

SUMMARY OF INVENTION

Briefly, this specification describes, in part, a compound of Formula(I):

or a pharmaceutically acceptable salt thereof, where:

Q is a cyclobutyl or cyclopentyl ring, each of which is optionallysubstituted by one hydroxy or methoxy group, or Q is an oxetanyl,tetrahydrofuranyl or oxanyl ring, each of which is optionallysubstituted by one methyl group;

R¹ is methyl;

R² is hydrogen or methyl; or R¹ and R² together form an azetidinyl,pyrrolidinyl or piperidinyl ring;

R³ is hydrogen or fluoro;

R⁴ is hydrogen or methyl; and

R⁵ is hydrogen or fluoro.

This specification also describes, in part, a pharmaceutical compositionwhich comprises a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablediluent or carrier.

This specification also describes, in part, a compound of formula (I),or a pharmaceutically acceptable salt thereof, for use in therapy.

This specification also describes, in part, a compound of formula (I),or a pharmaceutically acceptable salt thereof, for use in the treatmentof cancer.

This specification also describes, in part, a compound of formula (I),or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of cancer.

This specification also describes, in part, a method for treating cancerin a warm blooded animal in need of such treatment, which comprisesadministering to said warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: X-Ray Powder Diffraction Pattern of Form A of8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.

FIG. 2: DSC Thermogram of Form A of8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.

FIG. 3: Tumour Growth Inhibition in the Mouse Xenograft Model by8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one(Example 2) in Combination with Irinotecan.

FIG. 4: Tumour Growth Inhibition in the Mouse Xenograft Model by8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one(Example 1) in Combination with Irinotecan.

FIG. 5: Tumour Growth Inhibition in the Mouse Xenograft Model by8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one(Example 1) in Combination with Olaparib.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Many embodiments of the invention are detailed throughout thespecification and will be apparent to a reader skilled in the art. Theinvention is not to be interpreted as being limited to any particularembodiment(s) thereof.

In the first embodiment there is provided a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, where:

Q is a cyclobutyl or cyclopentyl ring, each of which is optionallysubstituted by one hydroxy or methoxy group, or Q is an oxetanyl,tetrahydrofuranyl or oxanyl ring, each of which is optionallysubstituted by one methyl group;

R¹ is methyl;

R² is hydrogen or methyl; or R¹ and R² together form an azetidinyl,pyrrolidinyl or piperidinyl ring;

R³ is hydrogen or fluoro;

R⁴ is hydrogen or methyl; and

R⁵ is hydrogen or fluoro.

The terms “cyclobutyl ring” and “cyclopentyl ring” refer to carbocyclicrings containing no heteroatoms. 1-methoxycyclobut-3-yl groups and3-methoxycyclobut-1-yl groups have the same structure, as shown below.

A cis-1-methoxy-cyclobut-3-yl group is equivalent to acis-3-methoxy-cyclobut-1-yl and has the following structure:

The same conventions apply to other cyclobutyl groups, for example1-hydroxycyclobut-3-yl groups and 3-hydroxycyclobut-1-yl groups.

In a similar fashion, 1-methoxycyclopent-3-yl groups and3-methoxycyclopent-1-yl groups have the same structure, as shown below.

The term “oxetanyl ring” includes oxetan-2-yl and oxetan-3-yl groups,the structures of which are shown below.

The term “tetrahydrofuranyl ring” includes tetrahydrofuran-2-yl andtetrahydrofuran-3-yl groups, the structures of which are shown below.

The term “oxanyl ring” includes oxan-2-yl, oxan-3-yl, and oxan-4-ylgroups, the structures of which are shown below.

In the above structures the dashed line indicates the bonding positionof the relevant group.

An oxanyl ring may also be referred to as a tetrahydropyranyl ring.Similarly, an oxan-4-yl ring may be referred to as atetrahydropyran-4-yl ring; an oxan-3-yl ring may be referred to as atetrahydropyran-3-yl ring, and an oxan-2-yl ring may be referred to as atetrahydropyran-2-yl ring.

Where it is mentioned that “R¹ and R² together form an azetidinyl,pyrrolidinyl or piperidinyl ring”, this means the R¹ and R² groups arejoined via a carbon-carbon covalent bond to form an unsubstitutedalkylene chain of the appropriate length for the corresponding ring. Forexample, when R¹ and R² together form a pyrrolidinyl ring, R¹ and R²together represent an unsubstituted butylene chain which is attached tothe relevant nitrogen atom in Formula (I) at both terminal carbons.

Where the term “optionally” is used, it is intended that the subsequentfeature may or may not occur. As such, use of the term “optionally”includes instances where the feature is present, and also instanceswhere the feature is not present. For example, a group “optionallysubstituted by one methoxy group” includes groups with and without amethoxy substituent.

The term “substituted” means that one or more hydrogens (for example 1or 2 hydrogens, or alternatively 1 hydrogen) on the designated group isreplaced by the indicated substituent(s) (for example 1 or 2substituents, or alternatively 1 substituent), provided that any atom(s)bearing a substituent maintains a permitted valency. Substituentcombinations encompass only stable compounds and stable syntheticintermediates. “Stable” means that the relevant compound or intermediateis sufficiently robust to be isolated and have utility either as asynthetic intermediate or as an agent having potential therapeuticutility. If a group is not described as “substituted”, or “optionallysubstituted”, it is to be regarded as unsubstituted (i.e. that none ofthe hydrogens on the designated group have been replaced).

The term “pharmaceutically acceptable” is used to specify that an object(for example a salt, dosage form, diluent or carrier) is suitable foruse in patients. An example list of pharmaceutically acceptable saltscan be found in the Handbook of Pharmaceutical Salts: Properties,Selection and Use, P. H. Stahl and C. G. Wermuth, editors,Weinheim/Zürich:Wiley-VCH/VHCA, 2002. A suitable pharmaceuticallyacceptable salt of a compound of Formula (I) is, for example, anacid-addition salt. An acid addition salt of a compound of Formula (I)may be formed by bringing the compound into contact with a suitableinorganic or organic acid under conditions known to the skilled person.An acid addition salt may for example be formed using an inorganic acidselected from the group consisting of hydrochloric acid, hydrobromicacid, sulphuric acid and phosphoric acid. An acid addition salt may alsobe formed using an organic acid selected from the group consisting oftrifluoroacetic acid, citric acid, maleic acid, oxalic acid, aceticacid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaricacid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonicacid and para-toluenesulfonic acid.

Therefore, in one embodiment there is provided a compound of Formula (I)or a pharmaceutically acceptable salt thereof, where thepharmaceutically acceptable salt is a hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citricacid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid,fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid,methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonic acidsalt. In one embodiment there is provided a compound of Formula (I) or apharmaceutically acceptable salt thereof, where the pharmaceuticallyacceptable salt is a trifluoroacetic acid, formic acid ormethanesulfonic acid salt. In one embodiment there is provided acompound of Formula (I) or a pharmaceutically acceptable salt thereof,where the pharmaceutically acceptable salt is a trifluoroacetic acid ormethanesulfonic acid salt. In one embodiment there is provided acompound of Formula (I) or a pharmaceutically acceptable salt thereof,where the pharmaceutically acceptable salt is a methanesulfonic acidsalt. In one embodiment there is provided a compound of Formula (I) or apharmaceutically acceptable salt thereof, where the pharmaceuticallyacceptable salt is a mono-methanesulfonic acid salt, i.e. thestoichiometry of the compound of the compound of Formula (I) tomethanesulfonic acid is 1:1.

A further embodiment provides any of the embodiments defined herein (forexample the embodiment of claim 1) with the proviso that one or morespecific Examples (for instance one, two or three specific Examples)selected from the group consisting of Examples 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70 and 71 is individually disclaimed.

Some values of variable groups in Formula (I) are as follows. Suchvalues may be used in combination with any of the definitions, claims(for example claim 1), or embodiments defined herein to provide furtherembodiments.

-   -   a) Q is a cyclobutyl or cyclopentyl ring, each of which is        substituted by one hydroxy or methoxy group, or Q is an        oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is        optionally substituted by one methyl group.    -   b) Q is a cyclobutyl ring substituted by one hydroxy or methoxy        group, or Q is an oxetanyl or oxanyl ring, each of which is        optionally substituted by one methyl group.    -   c) Q is a cyclobutyl ring substituted by one hydroxy or methoxy        group, or Q is an oxetanyl or oxanyl ring.    -   d) Q is cyclobutyl, 1-methoxy-cyclobut-3-yl,        1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl,        tetrahydrofuran-3-yl, oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl.    -   e) Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,        3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or        4-methyloxan-4-yl.    -   f) Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl or        oxan-4-yl.    -   g) Q is cis-1-methoxy-cyclobut-3-yl or oxan-4-yl.    -   h) Q is a cyclobutyl or cyclopentyl ring, each of which is        optionally substituted by one hydroxy or methoxy group.    -   i) Q is a cyclobutyl or cyclopentyl ring, each of which is        optionally substituted by one methoxy group.    -   j) Q is a cyclobutyl ring substituted by one hydroxy or methoxy        group.    -   k) Q is cyclobutyl, 1-hydroxy-cyclobut-3-yl or        1-methoxy-cyclobut-3-yl.    -   l) Q is cyclobutyl.    -   m) Q is a cyclopentyl ring substituted by one hydroxy or methoxy        group.    -   n) Q is a cyclopentyl ring substituted by one methoxy group.    -   o) Q is 3-methoxycyclopent-1-yl.    -   p) Q is 1-hydroxy-cyclobut-3-yl or 1-methoxy-cyclobut-3-yl.    -   q) Q is cis-1-hydroxy-cyclobut-3-yl or        cis-1-methoxy-cyclobut-3-yl.    -   r) Q is cis-1-methoxy-cyclobut-3-yl.    -   s) Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each of        which is optionally substituted by one methyl group.    -   t) Q is an oxetanyl or oxanyl ring, each of which is optionally        substituted by one methyl group.    -   u) Q is an oxetanyl or tetrahydrofuranyl ring.    -   v) Q is an oxetanyl ring.    -   w) Q is oxetan-3-yl.    -   x) Q is a tetrahydrofuranyl ring.    -   y) Q is tetrahydrofuran-3-yl.    -   z) Q is an oxanyl ring optionally substituted by one methyl        group.    -   aa) Q is an oxanyl ring.    -   bb) Q is oxan-4-yl.    -   cc) R¹ is methyl.    -   dd) R² is methyl.    -   ee) R² is hydrogen.    -   ff) R¹ is methyl and R² is hydrogen or methyl.    -   gg) R¹ and R² are both methyl; or R¹ and R² together form a        pyrrolidinyl ring.    -   hh) R¹ and R² are both methyl.    -   ii) R¹ and R² together form an azetidinyl, pyrrolidinyl or        piperidinyl ring.    -   jj) R¹ and R² together form an azetidinyl ring.    -   kk) R¹ and R² together form a pyrrolidinyl ring.    -   ll) R¹ and R² together form a piperidinyl ring.    -   mm) R³ and R⁵ are both hydrogen.    -   nn) R³ is hydrogen.    -   oo) R³ is fluoro.    -   pp) R⁴ is hydrogen.    -   qq) R⁴ is methyl.    -   rr) R⁵ is hydrogen.    -   ss) R⁵ is fluoro.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, where:

Q is cyclobutyl, 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, oxan-3-yl,oxan-4-yl or 4-methyloxan-4-yl;

R¹ is methyl;

R² is hydrogen or methyl; or R¹ and R² together form an azetidinyl,pyrrolidinyl or piperidinyl ring;

R³ is hydrogen or fluoro;

R⁴ is hydrogen or methyl; and

R⁵ is hydrogen or fluoro.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, where:

Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or4-methyloxan-4-yl;

R¹ is methyl;

R² is hydrogen or methyl; or R¹ and R² together form an azetidinyl,pyrrolidinyl or piperidinyl ring;

R³ is hydrogen or fluoro;

R⁴ is hydrogen or methyl; and

R⁵ is hydrogen or fluoro.

In one embodiment there is provided a compound of Formula (I), where:

Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl or3-methoxycyclopent-1-yl;

R¹ is methyl;

R² is hydrogen or methyl; or R¹ and R² together form an azetidinyl,pyrrolidinyl or piperidinyl ring;

R³ is hydrogen or fluoro;

R⁴ is hydrogen or methyl; and

R⁵ is hydrogen or fluoro.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, where:

Q is oxetan-3-yl, oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl;

R¹ is methyl;

R² is hydrogen or methyl; or R¹ and R² together form an azetidinyl,pyrrolidinyl or piperidinyl ring;

R³ is hydrogen or fluoro;

R⁴ is hydrogen or methyl; and

R⁵ is hydrogen or fluoro.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, where:

Q is cis-1-methoxy-cyclobut-3-yl or oxan-4-yl;

R¹ is methyl;

R² is methyl or hydrogen;

R³ is hydrogen;

R⁴ is methyl or hydrogen; and

R⁵ is hydrogen.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3    S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   1-(3-cis-Hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3    S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3    S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3    S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one;-   7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   3-Methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   1-(cis-3-Methoxycyclobutyl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one;-   1-(Oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one;-   3-Methyl-1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;    and-   1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-8-[6-[3-(methylamino)propoxy]-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3    S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3    S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-3-methyl-1-[(3    S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3    S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-(oxetan-3-yl)imidazo[4,5-c]quinolin-2-one;-   7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-2-one-   3-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3    S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-1-(oxetan-3-yl)-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   1-Cyclobutyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   1-Cyclobutyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]-3-pyridyl]-3-methyl-1-[(3    S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[2-Fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   1-[(1R,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   1-[(1S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   1-[(1S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   1-[(1R,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;    and-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   1-(3-cis-Hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3    S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one;-   7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   3-Methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   is    3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   1-(cis-3-Methoxycyclobutyl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one;-   1-(Oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one;-   3-Methyl-1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;    and-   1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   1-(3-cis-Hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3    S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   3-Methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;-   1-(cis-3-Methoxycyclobutyl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one;-   1-(Oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one;-   3-Methyl-1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one;-   3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one;    and-   1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one.-   In one embodiment, there is provided a compound of Formula (I), or a    pharmaceutically acceptable salt thereof, wherein the compound is    selected from the group consisting of:-   7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-8-[6-[3-(methylamino)propoxy]-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3    S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-3-methyl-1-[(3    S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3    S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-(oxetan-3-yl)imidazo[4,5-c]quinolin-2-one;-   7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-2-one-   13-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3    S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-1-(oxetan-3-yl)-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   1-Cyclobutyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   1-Cyclobutyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   3-Methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]-3-pyridyl]-3-methyl-1-[(3    S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[2-Fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   1-[(1R,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   1-[(1S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   1-[(1S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   1-[(1R,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one;    and-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one;    and-   8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one,or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a pharmaceutically acceptable saltof8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one,or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.

In one embodiment there is provided a pharmaceutically acceptable saltof8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.

In one embodiment there is provided1-(cis-3-methoxycyclobutyl)-3-methyl-8-{6-[3-(pyrrolidin-1-yl)propoxy]pyridin-3-yl}-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one,or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided1-(cis-3-methoxycyclobutyl)-3-methyl-8-{6-[3-(pyrrolidin-1-yl)propoxy]pyridin-3-yl}-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a pharmaceutically acceptable saltof1-(cis-3-methoxycyclobutyl)-3-methyl-8-{6-[3-(pyrrolidin-1-yl)propoxy]pyridin-3-yl}-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one.

Compounds and salts described in this specification may exist insolvated forms and unsolvated forms. For example, a solvated form may bea hydrated form, such as a hemi-hydrate, a mono-hydrate, a di-hydrate, atri-hydrate or an alternative quantity thereof. The inventionencompasses all such solvated and unsolvated forms of compounds ofFormula (I), particularly to the extent that such forms possess ATMkinase inhibitory activity, as for example measured using the testsdescribed herein.

Atoms of the compounds and salts described in this specification mayexist as their isotopes. The invention encompasses all compounds ofFormula (I) where an atom is replaced by one or more of its isotopes(for example a compound of Formula (I) where one or more carbon atom isan ¹¹C or ¹³C carbon isotope, or where one or more hydrogen atoms is a²H or ³H isotope, or where one of more fluorine atoms is an ¹⁸Fisotope).

Compounds and salts described in this specification may exist as amixture of tautomers. “Tautomers” are structural isomers that exist inequilibrium resulting from the migration of a hydrogen atom. Theinvention includes all tautomers of compounds of Formula (I)particularly to the extent that such tautomers possess ATM kinaseinhibitory activity.

Compounds and salts described in this specification may exist inoptically active or racemic forms by virtue of one or more asymmetriccarbon atoms. The invention includes any optically active or racemicform of a compound of Formula (I) which possesses ATM kinase inhibitoryactivity, as for example measured using the tests described herein. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis using optically active materials or by resolution of a racemicform.

Therefore, in one embodiment there is provided a compound of Formula(I), or a pharmaceutically acceptable salt thereof, which is a singleoptical isomer being in an enantiomeric excess (% ee) of ≥95%, ≥98% or≥99%. In one embodiment, the single optical isomer is present in anenantiomeric excess (% ee) of ≥99%.

Compounds and salts described in this specification may be crystalline,and may exhibit one or more crystalline forms. The invention encompassesany crystalline or amorphous form of a compound of Formula (I), ormixture of such forms, which possesses ATM kinase inhibitory activity.

It is generally known that crystalline materials may be characterisedusing conventional techniques such as X-Ray Powder Diffraction (XRPD),Differential Scanning calorimetry (DSC), Thermal Gravimetric Analysis(TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT)spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solidstate nuclear magnetic resonance spectroscopy. The water content of suchcrystalline materials may be determined by Karl Fischer analysis.

The specific solid forms described herein provide XRPD patternssubstantially the same as the XRPD patterns shown in the Figures, andhave the various 2-theta values as shown in the Tables included herein.One skilled in the art will understand that an XRPD pattern ordiffractogram may be obtained which has one or more measurement errorsdepending on the recording conditions, such as the equipment or machineused. Similarly, it is generally known that intensities in an XRPDpattern may fluctuate depending on measurement conditions or samplepreparation as a result of preferred orientation. Persons skilled in theart of XRPD will further realise that the relative intensity of peakscan also be affected by, for example, grains above 30 μm in size andnon-unitary aspect ratios. The skilled person understands that theposition of reflections can be affected by the precise height at whichthe sample sits in the diffractometer, and also the zero calibration ofthe diffractometer. The surface planarity of the sample may also have asmall effect.

As a result of these considerations, the diffraction pattern datapresented are not to be taken as absolute values (Jenkins, R & Snyder,R. L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons1996; Bunn, C. W. (1948), ‘Chemical Crystallography’, Clarendon Press,London; Klug, H. P. & Alexander, L. E. (1974), ‘X-Ray DiffractionProcedures’). It should correspondingly be understood that the solidforms are not limited to the crystals that provide XRPD patterns thatare identical to the XRPD pattern shown in the Figures, and any crystalsproviding XRPD patterns substantially the same as those shown in theFigures fall within the scope of the invention. A person skilled in theart of XRPD is able to judge the substantial identity of XRPD patterns.Generally, a measurement error of a diffraction angle in an XRPD isapproximately plus or minus 0.2° 2-theta, and such degree of ameasurement error should be taken into account when considering theX-ray powder diffraction pattern in the Figures and when reading datacontained in the Tables included herein.

The compound of Example 1 exhibits crystalline properties, and onecrystalline form has been characterised.

Therefore, in one embodiment there is provided Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at about 2-theta=3.90.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at about 2-theta=11.6°.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least two specificpeaks at about 2-theta=3.9 and 11.6°.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one,which has an X-ray powder diffraction pattern with specific peaks atabout 2-theta=3.9, 7.7, 10.7, 11.6, 15.4, 16.9, 17.4, 18.4, 21.3 and22.2°.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-onewhich has an X-ray powder diffraction pattern substantially the same asthe X-ray powder diffraction pattern shown in FIG. 1.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at 2-theta=3.9° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at 2-theta=11.6° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least two specificpeaks at 2-theta=3.9 and 11.6° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one,which has an X-ray powder diffraction pattern with specific peaks at2-theta=3.9, 7.7, 10.7, 11.6, 15.4, 16.9, 17.4, 18.4, 21.3 and 22.2°plus or minus 0.2° 2-theta.

DSC analysis of Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-oneshows a melting endotherm with an onset of 212.3° C. and a peak at214.1° C. (FIG. 2).

A person skilled in the art understands that the value or range ofvalues observed in a particular compound's DSC Thermogram will showvariation between batches of different purities. Therefore, whilst forone compound the range may be small, for others the range may be quitelarge. Generally, a measurement error of a diffraction angle in DSCthermal events is approximately plus or minus 5° C., and such degree ofa measurement error should be taken into account when considering theDSC data included herein.

Therefore, in one embodiment there is provided a crystalline form, FormA of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-onewhich has a DSC endotherm with an onset of melting at about 212.3° C.and a peak at about 214.1° C.

Therefore, in one embodiment there is provided a crystalline form, FormA of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-onewhich has a DSC endotherm with an onset of melting at 212.3° C. plus orminus 5° C. and a peak at 214.1° C. plus or minus 5° C.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-onewhich has a DSC endotherm with an onset of melting at 212.3° C. and apeak at 214.1° C.

In one embodiment there is provided a crystalline form, Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-onewhich has a DSC thermogram substantially as shown in FIG. 2.

When it is stated that an embodiment relates to a crystalline form, thedegree of crystallinity may be greater than about 60%. In someembodiments the degree of crystallinity is greater than about 80%. Insome embodiments the degree of crystallinity is greater than about 90%.In some embodiments the degree of crystallinity is greater than about95%. In some embodiments the degree of crystallinity is greater thanabout 98%.

Compounds of Formula (I) may for example be prepared by the reaction ofa compound of Formula (II):

Or a salt thereof, where Q, R³, R⁴ and R⁵ are as defined in any of theembodiments herein and X is a leaving group (for example a halogen atom,or alternatively a fluorine atom) with a compound of formula (III):

Or a salt thereof, where R¹ and R² are as defined in any of theembodiments herein. The reaction is conveniently performed in a suitablesolvent (for example DMF, DMA or THF) and in the presence of a base (forexample sodium hydride) at a suitable temperature (for example atemperature in the range of about 20-50° C.).

Compounds of Formula (II), and salts thereof, are therefore useful asintermediates in the preparation of the compounds of Formula (I) andprovide a further embodiment.

In one embodiment there is provided a compound of Formula (II), or asalt thereof, where:

Q is a cyclobutyl or cyclopentyl ring, each of which is optionallysubstituted by one hydroxy or methoxy group, or Q is an oxetanyl,tetrahydrofuranyl or oxanyl ring, each of which is optionallysubstituted by one methyl group;

R³ is hydrogen or fluoro;

R⁴ is hydrogen or methyl;

R⁵ is hydrogen or fluoro; and

X is a leaving group. In one embodiment X is a halogen atom or atriflate group. In one embodiment X is a fluorine atom.

In one embodiment there is provided a compound of Formula (II), or asalt thereof, where:

Q is cyclobutyl, 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, oxan-3-yl,oxan-4-yl or 4-methyloxan-4-yl;

R³ is hydrogen or fluoro;

R⁴ is hydrogen or methyl;

R⁵ is hydrogen or fluoro; and

X is a leaving group. In one embodiment X is a halogen atom or atriflate group. In one embodiment X is a fluorine atom.

In one embodiment there is provided a compound of Formula (II), or asalt thereof, where:

Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or4-methyloxan-4-yl;

R³ is hydrogen or fluoro;

R⁴ is hydrogen or methyl;

R⁵ is hydrogen or fluoro; and

X is a leaving group. In one embodiment X is a halogen atom or atriflate group. In one embodiment X is a fluorine atom.

In one embodiment there is provided8-(6-fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one,or a salt thereof.

In one embodiment there is provided8-(6-fluoropyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one,or a salt thereof.

In any of the embodiments where a compound of Formula (II) or a saltthereof is mentioned it is to be understood that such salts do not needto be pharmaceutically acceptable salts. A suitable salt of a compoundof Formula (II) is, for example, an acid-addition salt. An acid additionsalt of a compound of Formula (II) may be formed by bringing thecompound into contact with a suitable inorganic or organic acid underconditions known to the skilled person. An acid addition salt may forexample be formed using an inorganic acid selected from the groupconsisting of hydrochloric acid, hydrobromic acid, sulphuric acid andphosphoric acid. An acid addition salt may also be formed using anorganic acid selected from the group consisting of trifluoroacetic acid,citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoicacid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvicacid, methanesulfonic acid, benzenesulfonic acid andpara-toluenesulfonic acid.

Therefore, in one embodiment there is provided a compound of Formula(II) or a salt thereof, where the salt is a hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid,citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoicacid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvicacid, methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonicacid salt.

The compounds of Formula (II) may for example be prepared by thereaction of a compound of Formula (IV):

Where Q, R⁴ and R⁵ are as defined in any of the embodiments herein andX¹ is a leaving group (for example an iodine, bromine, or chlorine atomor a triflate group, or alternatively a bromine atom) with a compound offormula (V):

Or a salt thereof, where R³ and X are as defined in any of theembodiments herein and Y is a boronic acid, boronic ester or potassiumtrifluoroborate group (for example boronic acid, boronic acid pinacolester, or potassium trifluoroborate). The reaction may be performedunder standard conditions well known to those skilled in the art, forexample in the presence of a palladium source (for example tetrakistriphenylphosphine palladium or palladium(II) acetate), optionally aphosphine ligand (for example Xantphos or S-phos), and a suitable base(for example cesium carbonate or triethylamine).

Compounds of Formula (IV) are therefore useful as intermediates in thepreparation of the compounds of Formula (I) and provide a furtherembodiment.

In one embodiment there is provided a compound of Formula (IV), or asalt thereof, where:

Q is a cyclobutyl or cyclopentyl ring, each of which is optionallysubstituted by one hydroxy or methoxy group, or Q is an oxetanyl,tetrahydrofuranyl or oxanyl ring, each of which is optionallysubstituted by one methyl group;

R⁴ is hydrogen or methyl;

R⁵ is hydrogen or fluoro; and

X¹ is a leaving group. In one embodiment X¹ is an iodine, bromine, orchlorine atom or a triflate group. In one embodiment X¹ is a bromineatom.

In one embodiment there is provided a compound of Formula (IV), or asalt thereof, where:

Q is cyclobutyl, 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, oxan-3-yl,oxan-4-yl or 4-methyloxan-4-yl;

R⁴ is hydrogen or methyl;

R⁵ is hydrogen or fluoro; and

X¹ is a leaving group. In one embodiment X¹ is an iodine, bromine, orchlorine atom or a triflate group. In one embodiment X¹ is a bromineatom.

In one embodiment there is provided a compound of Formula (IV), or asalt thereof, where:

Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or4-methyloxan-4-yl;

R⁴ is hydrogen or methyl;

R⁵ is hydrogen or fluoro; and

X¹ is a leaving group. In one embodiment X¹ is an iodine, bromine, orchlorine atom or a triflate group. In one embodiment X¹ is a bromineatom.

In one embodiment there is provided8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.

In one embodiment there is provided8-bromo-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one.

Compounds of formula (IV) can be prepared by methods similar to thoseshown in the Examples section.

Compounds of Formula (I) may also be prepared by the reaction of acompound of Formula (IV) as described above with a compound of formula(VI):

Where R¹, R² and R³ are as defined in any of the embodiments herein andY is a boronic acid, boronic ester or potassium trifluoroborate group(for example boronic acid, boronic acid pinacol ester, or potassiumtrifluoroborate). The reaction may be performed under standardconditions well known to those skilled in the art, for example in thepresence of a palladium source (for example tetrakis triphenylphosphinepalladium or palladium(II) acetate), optionally a phosphine ligand (forexample Xantphos or S-phos), and a suitable base (for example cesiumcarbonate or triethylamine).

Compounds of formula (VI) can be prepared by methods similar to thoseshown in the Examples section.

As a result of their ATM kinase inhibitory activity, the compounds ofFormula (I), and pharmaceutically acceptable salts thereof are expectedto be useful in therapy, for example in the treatment of diseases ormedical conditions mediated at least in part by ATM kinase, includingcancer.

Where “cancer” is mentioned, this includes both non-metastatic cancerand also metastatic cancer, such that treating cancer involves treatmentof both primary tumours and also tumour metastases.

“ATM kinase inhibitory activity” refers to a decrease in the activity ofATM kinase as a direct or indirect response to the presence of acompound of Formula (I), or pharmaceutically acceptable salt thereof,relative to the activity of ATM kinase in the absence of compound ofFormula (I), or pharmaceutically acceptable salt thereof. Such adecrease in activity may be due to the direct interaction of thecompound of Formula (I), or pharmaceutically acceptable salt thereofwith ATM kinase, or due to the interaction of the compound of Formula(I), or pharmaceutically acceptable salt thereof with one or more otherfactors that in turn affect ATM kinase activity. For example, thecompound of Formula (I), or pharmaceutically acceptable salt thereof maydecrease ATM kinase by directly binding to the ATM kinase, by causing(directly or indirectly) another factor to decrease ATM kinase activity,or by (directly or indirectly) decreasing the amount of ATM kinasepresent in the cell or organism.

The term “therapy” is intended to have its normal meaning of dealingwith a disease in order to entirely or partially relieve one, some orall of its symptoms, or to correct or compensate for the underlyingpathology. The term “therapy” also includes “prophylaxis” unless thereare specific indications to the contrary. The terms “therapeutic” and“therapeutically” should be interpreted in a corresponding manner.

The term “prophylaxis” is intended to have its normal meaning andincludes primary prophylaxis to prevent the development of the diseaseand secondary prophylaxis whereby the disease has already developed andthe patient is temporarily or permanently protected against exacerbationor worsening of the disease or the development of new symptomsassociated with the disease.

The term “treatment” is used synonymously with “therapy”. Similarly theterm “treat” can be regarded as “applying therapy” where “therapy” is asdefined herein.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in therapy.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment of adisease mediated by ATM kinase. In one embodiment, said disease mediatedby ATM kinase is cancer. In one embodiment, said cancer is selected fromthe group consisting of colorectal cancer, glioblastoma, gastric cancer,ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocyticleukaemia, acute myeloid leukaemia, head and neck squamous cellcarcinoma, breast cancer, hepatocellular carcinoma, small cell lungcancer and non-small cell lung cancer. In one embodiment, said cancer isselected from the group consisting of colorectal cancer, glioblastoma,gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chroniclymphocytic leukaemia, head and neck squamous cell carcinoma and lungcancer. In one embodiment, said cancer is colorectal cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofHuntingdon's disease.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of a disease mediated by ATM kinase.In one embodiment, said disease mediated by ATM kinase is cancer. In oneembodiment, said cancer is selected from the group consisting ofcolorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuselarge B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloidleukaemia, head and neck squamous cell carcinoma, breast cancer,hepatocellular carcinoma, small cell lung cancer and non-small cell lungcancer. In one embodiment, said cancer is selected from the groupconsisting of colorectal cancer, glioblastoma, gastric cancer, ovariancancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia,head and neck squamous cell carcinoma and lung cancer. In oneembodiment, said cancer is colorectal cancer.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of cancer.

In one embodiment there is provided a method for treating a disease inwhich inhibition of ATM kinase is beneficial in a warm-blooded animal inneed of such treatment, which comprises administering to saidwarm-blooded animal a therapeutically effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. In oneembodiment, said disease is cancer. In one embodiment, said cancer isselected from the group consisting of colorectal cancer, glioblastoma,gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chroniclymphocytic leukaemia, acute myeloid leukaemia, head and neck squamouscell carcinoma, breast cancer, hepatocellular carcinoma, small cell lungcancer and non-small cell lung cancer. In one embodiment, said cancer isselected from the group consisting of colorectal cancer, glioblastoma,gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chroniclymphocytic leukaemia, head and neck squamous cell carcinoma and lungcancer. In one embodiment, said cancer is colorectal cancer.

The term “therapeutically effective amount” refers to an amount of acompound of Formula (I) as described in any of the embodiments hereinwhich is effective to provide “therapy” in a subject, or to “treat” adisease or disorder in a subject. In the case of cancer, thetherapeutically effective amount may cause any of the changes observableor measurable in a subject as described in the definition of “therapy”,“treatment” and “prophylaxis” above. For example, the effective amountcan reduce the number of cancer or tumour cells; reduce the overalltumour size; inhibit or stop tumour cell infiltration into peripheralorgans including, for example, the soft tissue and bone; inhibit andstop tumour metastasis; inhibit and stop tumour growth; relieve to someextent one or more of the symptoms associated with the cancer; reducemorbidity and mortality; improve quality of life; or a combination ofsuch effects. An effective amount may be an amount sufficient todecrease the symptoms of a disease responsive to inhibition of ATMkinase activity. For cancer therapy, efficacy in-vivo can, for example,be measured by assessing the duration of survival, time to diseaseprogression (TTP), the response rates (RR), duration of response, and/orquality of life. As recognized by those skilled in the art, effectiveamounts may vary depending on route of administration, excipient usage,and co-usage with other agents. For example, where a combination therapyis used, the amount of the compound of formula (I) or pharmaceuticallyacceptable salt described in this specification and the amount of theother pharmaceutically active agent(s) are, when combined, jointlyeffective to treat a targeted disorder in the animal patient. In thiscontext, the combined amounts are in a “therapeutically effectiveamount” if they are, when combined, sufficient to decrease the symptomsof a disease responsive to inhibition of ATM activity as describedabove. Typically, such amounts may be determined by one skilled in theart by, for example, starting with the dosage range described in thisspecification for the compound of formula (I) or pharmaceuticallyacceptable salt thereof and an approved or otherwise published dosagerange(s) of the other pharmaceutically active compound(s).

“Warm-blooded animals” include, for example, humans.

In one embodiment there is provided a method for treating cancer in awarm-blooded animal in need of such treatment, which comprisesadministering to said warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof. In one embodiment, said cancer is selected from the groupconsisting of colorectal cancer, glioblastoma, gastric cancer, ovariancancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia,acute myeloid leukaemia, head and neck squamous cell carcinoma, breastcancer, hepatocellular carcinoma, small cell lung cancer and non-smallcell lung cancer. In one embodiment, said cancer is selected from thegroup consisting of colorectal cancer, glioblastoma, gastric cancer,ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocyticleukaemia, head and neck squamous cell carcinoma and lung cancer. In oneembodiment, said cancer is colorectal cancer.

In any embodiment where cancer is mentioned in a general sense, saidcancer may be selected from the group consisting of colorectal cancer,glioblastoma, gastric cancer, ovarian cancer, diffuse large B-celllymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, headand neck squamous cell carcinoma, breast cancer, hepatocellularcarcinoma, small cell lung cancer and non-small cell lung cancer. Saidcancer may also be selected from the group consisting of colorectalcancer, glioblastoma, gastric cancer, ovarian cancer, diffuse largeB-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamouscell carcinoma and lung cancer.

In any embodiment where cancer is mentioned in a general sense thefollowing embodiments may apply:

In one embodiment the cancer is colorectal cancer.

In one embodiment the cancer is glioblastoma.

In one embodiment the cancer is gastric cancer.

In one embodiment the cancer is oesophageal cancer.

In one embodiment the cancer is ovarian cancer.

In one embodiment the cancer is endometrial cancer.

In one embodiment the cancer is cervical cancer.

In one embodiment the cancer is diffuse large B-cell lymphoma.

In one embodiment the cancer is chronic lymphocytic leukaemia.

In one embodiment the cancer is acute myeloid leukaemia.

In one embodiment the cancer is head and neck squamous cell carcinoma.

In one embodiment the cancer is breast cancer. In one embodiment thecancer is triple negative breast cancer.

“Triple negative breast cancer” is any breast cancer that does notexpress the genes for the oestrogen receptor, progesterone receptor andHer2/neu.

In one embodiment the cancer is hepatocellular carcinoma.

In one embodiment the cancer is lung cancer. In one embodiment the lungcancer is small cell lung cancer. In one embodiment the lung cancer isnon-small cell lung cancer.

In one embodiment the cancer is metastatic cancer. In one embodiment themetastatic cancer comprises metastases of the central nervous system. Inone embodiment the metastases of the central nervous system comprisebrain metastases. In one embodiment the metastases of the centralnervous system comprise leptomeningeal metastases.

“Leptomeningeal metastases” occur when cancer spreads to the meninges,the layers of tissue that cover the brain and the spinal cord.Metastases can spread to the meninges through the blood or they cantravel from brain metastases, carried by the cerebrospinal fluid (CSF)that flows through the meninges. In one embodiment the cancer isnon-metastatic cancer. The anti-cancer treatment described in thisspecification may be useful as a sole therapy, or may involve, inaddition to administration of the compound of Formula (I), conventionalsurgery, radiotherapy or chemotherapy; or a combination of suchadditional therapies. Such conventional surgery, radiotherapy orchemotherapy may be administered simultaneously, sequentially orseparately to treatment with the compound of Formula (I).

Radiotherapy may include one or more of the following categories oftherapy:

-   -   i. External radiation therapy using electromagnetic radiation,        and intraoperative radiation therapy using electromagnetic        radiation;    -   ii. Internal radiation therapy or brachytherapy; including        interstitial radiation therapy or intraluminal radiation        therapy; or    -   iii. Systemic radiation therapy, including but not limited to        iodine 131 and strontium 89.

Therefore, in one embodiment there is provided a compound of Formula(I), or a pharmaceutically acceptable salt thereof, and radiotherapy,for use in the treatment of cancer. In one embodiment the cancer isglioblastoma. In one embodiment, the cancer is metastatic cancer. In oneembodiment the metastatic cancer comprises metastases of the centralnervous system. In one embodiment the metastases of the central nervoussystem comprise brain metastases. In one embodiment the metastases ofthe central nervous system comprise leptomeningeal metastases.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination withradiotherapy. In one embodiment the cancer is glioblastoma. In oneembodiment, the cancer is metastatic cancer. In one embodiment themetastatic cancer comprises metastases of the central nervous system. Inone embodiment the metastases of the central nervous system comprisebrain metastases. In one embodiment the metastases of the centralnervous system comprise leptomeningeal metastases.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and radiotherapy, for use inthe simultaneous, separate or sequential treatment of cancer. In oneembodiment the cancer is selected from glioblastoma, lung cancer (forexample small cell lung cancer or non-small cell lung cancer), breastcancer (for example triple negative breast cancer), head and necksquamous cell carcinoma, oesophageal cancer, cervical cancer andendometrial cancer. In one embodiment the cancer is glioblastoma. In oneembodiment, the cancer is metastatic cancer. In one embodiment themetastatic cancer comprises metastases of the central nervous system. Inone embodiment the metastases of the central nervous system comprisebrain metastases. In one embodiment the metastases of the centralnervous system comprise leptomeningeal metastases.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered simultaneously, separately orsequentially with radiotherapy. In one embodiment the cancer is selectedfrom glioblastoma, lung cancer (for example small cell lung cancer ornon-small cell lung cancer), breast cancer (for example triple negativebreast cancer), head and neck squamous cell carcinoma, oesophagealcancer, cervical cancer and endometrial cancer. In one embodiment thecancer is glioblastoma. In one embodiment, the cancer is metastaticcancer. In one embodiment the metastatic cancer comprises metastases ofthe central nervous system. In one embodiment the metastases of thecentral nervous system comprise brain metastases. In one embodiment themetastases of the central nervous system comprise leptomeningealmetastases.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof and radiotherapy, wherein thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,and radiotherapy are jointly effective in producing an anti-cancereffect. In one embodiment the cancer is selected from glioblastoma, lungcancer (for example small cell lung cancer or non-small cell lungcancer), breast cancer (for example triple negative breast cancer), headand neck squamous cell carcinoma, oesophageal cancer, cervical cancerand endometrial cancer. In one embodiment the cancer is glioblastoma. Inone embodiment, the cancer is metastatic cancer. In one embodiment themetastatic cancer comprises metastases of the central nervous system. Inone embodiment the metastases of the central nervous system comprisebrain metastases. In one embodiment the metastases of the centralnervous system comprise leptomeningeal metastases.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof and simultaneously,separately or sequentially administering radiotherapy, wherein thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,and radiotherapy are jointly effective in producing an anti-cancereffect. In one embodiment the cancer is glioblastoma. In one embodiment,the cancer is metastatic cancer. In one embodiment the metastatic cancercomprises metastases of the central nervous system. In one embodimentthe metastases of the central nervous system comprise brain metastases.In one embodiment the metastases of the central nervous system compriseleptomeningeal metastases.

In any embodiment the radiotherapy is selected from the group consistingof one or more of the categories of radiotherapy listed under points(i)-(iii) above.

Chemotherapy may include one or more of the following categories ofanti-tumour substance:

-   -   i. Antineoplastic agents and combinations thereof, such as DNA        alkylating agents (for example cisplatin, oxaliplatin,        carboplatin, cyclophosphamide, nitrogen mustards like        ifosfamide, bendamustine, melphalan, chlorambucil, busulphan,        temozolamide and nitrosoureas like carmustine); antimetabolites        (for example gemcitabine and antifolates such as        fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,        methotrexate, cytosine arabinoside, and hydroxyurea);        anti-tumour antibiotics (for example anthracyclines like        adriamycin, bleomycin, doxorubicin, liposomal doxorubicin,        pirarubicin, daunomycin, valrubicin, epirubicin, idarubicin,        mitomycin-C, dactinomycin, amrubicin and mithramycin);        antimitotic agents (for example vinca alkaloids like        vincristine, vinblastine, vindesine and vinorelbine and taxoids        like taxol and taxotere and polokinase inhibitors); and        topoisomerase inhibitors (for example epipodophyllotoxins like        etoposide and teniposide, amsacrine, irinotecan, topotecan and        camptothecin); inhibitors of DNA repair mechanisms such as CHK        kinase; DNA-dependent protein kinase inhibitors; inhibitors of        poly (ADP-ribose) polymerase (PARP inhibitors, including        olaparib); and Hsp90 inhibitors such as tanespimycin and        retaspimycin, inhibitors of ATR kinase (such as AZD6738); and        inhibitors of WEE1 kinase (such as AZD1775/MK-1775);    -   ii. Antiangiogenic agents such as those that inhibit the effects        of vascular endothelial growth factor, for example the        anti-vascular endothelial cell growth factor antibody        bevacizumab and for example, a VEGF receptor tyrosine kinase        inhibitor such as vandetanib (ZD6474), sorafenib, vatalanib        (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib        (GW 786034) and cediranib (AZD2171); compounds such as those        disclosed in International Patent Applications WO97/22596, WO        97/30035, WO 97/32856 and WO 98/13354; and compounds that work        by other mechanisms (for example linomide, inhibitors of        integrin αvβ3 function and angiostatin), or inhibitors of        angiopoietins and their receptors (Tie-1 and Tie-2), inhibitors        of PLGF, inhibitors of delta-like ligand (DLL-4);    -   iii. Immunotherapy approaches, including for example ex-vivo and        in-vivo approaches to increase the immunogenicity of patient        tumour cells, such as transfection with cytokines such as        interleukin 2, interleukin 4 or granulocyte-macrophage colony        stimulating factor; approaches to decrease T-cell anergy or        regulatory T-cell function; approaches that enhance T-cell        responses to tumours, such as blocking antibodies to CTLA4 (for        example ipilimumab and tremelimumab), B7H1, PD-1 (for example        BMS-936558 or AMP-514), PD-L1 (for example MEDI4736) and agonist        antibodies to CD137; approaches using transfected immune cells        such as cytokine-transfected dendritic cells; approaches using        cytokine-transfected tumour cell lines, approaches using        antibodies to tumour associated antigens, and antibodies that        deplete target cell types (e.g., unconjugated anti-CD20        antibodies such as Rituximab, radiolabeled anti-CD20 antibodies        Bexxar and Zevalin, and anti-CD54 antibody Campath); approaches        using anti-idiotypic antibodies; approaches that enhance Natural        Killer cell function; and approaches that utilize antibody-toxin        conjugates (e.g. anti-CD33 antibody Mylotarg); immunotoxins such        as moxetumumab pasudotox; agonists of toll-like receptor 7 or        toll-like receptor 9;    -   iv. Efficacy enhancers, such as leucovorin.

Therefore, in one embodiment there is provided a compound of Formula(I), or a pharmaceutically acceptable salt thereof, and at least oneadditional anti-tumour substance, for use in the treatment of cancer. Inone embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered in combination with anadditional anti-tumour substance. In one embodiment there is oneadditional anti-tumour substance. In one embodiment there are twoadditional anti-tumour substances. In one embodiment there are three ormore additional anti-tumour substances.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance for use in the simultaneous, separate orsequential treatment of cancer. In one embodiment there is provided acompound of Formula (I), or a pharmaceutically acceptable salt thereof,for use in the treatment of cancer, where the compound of Formula (I),or a pharmaceutically acceptable salt thereof, is administeredsimultaneously, separately or sequentially with an additionalanti-tumour substance.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof and at least one additionalanti-tumour substance, wherein the amounts of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, and the additionalanti-tumour substance are jointly effective in producing an anti-cancereffect.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof, and simultaneously,separately or sequentially administering at least one additionalanti-tumour substance to said warm-blooded animal, wherein the amountsof the compound of Formula (I), or pharmaceutically acceptable saltthereof, and the additional anti-tumour substance are jointly effectivein producing an anti-cancer effect.

In any embodiment the additional anti-tumour substance is selected fromthe group consisting of one or more of the anti-tumour substances listedunder points (i)-(iv) above.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least oneanti-neoplastic agent for use in the treatment of cancer. In oneembodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with at leastone anti-neoplastic agent. In one embodiment the anti-neoplastic agentis selected from the list of antineoplastic agents in point (i) above.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least oneanti-neoplastic agent for use in the simultaneous, separate orsequential treatment of cancer. In one embodiment there is provided acompound of Formula (I), or a pharmaceutically acceptable salt thereof,for use in the treatment of cancer, where the compound of Formula (I),or a pharmaceutically acceptable salt thereof, is administeredsimultaneously, separately or sequentially with at least oneanti-neoplastic agent. In one embodiment the antineoplastic agent isselected from the list of antineoplastic agents in point (i) above.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance selected from the group consisting of cisplatin,oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin,pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide,mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide,carmustine, melphalan, bleomycin, olaparib, MEDI4736, AZD1775 andAZD6738, for use in the treatment of cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance selected from the group consisting of cisplatin,oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan,topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine,chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan,bleomycin, olaparib, AZD1775 and AZD6738, for use in the treatment ofcancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with at leastone additional anti-tumour substance selected from the group consistingof cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin,doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin,etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide,ifosfamide, carmustine, melphalan, bleomycin, olaparib, MEDI4736,AZD1775 and AZD6738.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance selected from the group consisting of doxorubicin,irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil,cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin andolaparib for use in the treatment of cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with at leastone additional anti-tumour substance selected from the group consistingof doxorubicin, irinotecan, topotecan, etoposide, mitomycin,bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine,melphalan, bleomycin and olaparib.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance selected from the group consisting of doxorubicin,irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil,cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin, foruse in the treatment of cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with at leastone additional anti-tumour substance selected from the group consistingof doxorubicin, irinotecan, topotecan, etoposide, mitomycin,bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine,melphalan and bleomycin.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with at leastone additional anti-tumour substance selected from the group consistingof doxorubicin, pirarubicin, amrubicin and epirubicin. In one embodimentthe cancer is acute myeloid leukaemia. In one embodiment the cancer isbreast cancer (for example triple negative breast cancer). In oneembodiment the cancer is hepatocellular carcinoma.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and irinotecan, for use in thetreatment of cancer. In one embodiment there is provided a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment of cancer, where the compound of Formula (I), or apharmaceutically acceptable salt thereof, is administered in combinationwith irinotecan. In one embodiment the cancer is colorectal cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and FOLFIRI, for use in thetreatment of cancer. In one embodiment there is provided a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment of cancer, where the compound of Formula (I), or apharmaceutically acceptable salt thereof, is administered in combinationwith FOLFIRI. In one embodiment the cancer is colorectal cancer.

FOLFIRI is a dosage regime involving a combination of leucovorin,5-fluorouracil and irinotecan.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with olaparib.In one embodiment the cancer is gastric cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with topotecan.In one embodiment the cancer is small cell lung cancer. In oneembodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination withimmunotherapy. In one embodiment the immunotherapy is one or more of theagents listed under point (iii) above. In one embodiment theimmunotherapy is an anti-PD-L1 antibody (for example MEDI4736).

In one embodiment there is provided a pharmaceutical compositioncomprising a compound of Formula (I) and at least one additionalanti-tumour substance. In one embodiment the pharmaceutical compositionalso comprises at least one pharmaceutically acceptable diluent orcarrier. In one embodiment the anti-tumour substance is ananti-neoplastic agent.

In one embodiment there is provided a pharmaceutical compositioncomprising a compound of Formula (I) and at least one additionalanti-tumour substance, for use in the treatment of cancer. In oneembodiment the pharmaceutical composition also comprises at least onepharmaceutically acceptable diluent or carrier. In one embodiment theanti-tumour substance is an anti-neoplastic agent.

According to a further embodiment there is provided a kit comprising:

a) A compound of formula (I), or a pharmaceutically acceptable saltthereof, in a first unit dosage form;

b) A further additional anti-tumour substance in a further unit dosageform;

c) Container means for containing said first and further unit dosageforms; and optionally

d) Instructions for use. In one embodiment the anti-tumour substancecomprises an anti-neoplastic agent.

In any embodiment where an anti-neoplastic agent is mentioned, theanti-neoplastic agent is one or more of the agents listed under point(i) above.

The compounds of Formula (I), and pharmaceutically acceptable saltsthereof, may be administered as pharmaceutical compositions, comprisingone or more pharmaceutically acceptable diluents or carriers.

Therefore, in one embodiment there is provided a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablediluent or carrier.

The compositions may be in a form suitable for oral use (for example astablets, lozenges, hard or soft capsules, aqueous or oily suspensions,emulsions, dispersible powders or granules, syrups or elixirs), fortopical use (for example as creams, ointments, gels, or aqueous or oilysolutions or suspensions), for administration by inhalation (for exampleas a finely divided powder or a liquid aerosol), for administration byinsufflation (for example as a finely divided powder) or for parenteraladministration (for example as a sterile aqueous or oily solution forintravenous, subcutaneous, intramuscular or intramuscular dosing), or asa suppository for rectal dosing. The compositions may be obtained byconventional procedures using conventional pharmaceutical excipients,well known in the art. Thus, compositions intended for oral use maycontain, for example, one or more colouring, sweetening, flavouringand/or preservative agents.

In one embodiment there is provided a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable diluent orcarrier, for use in therapy.

In one embodiment there is provided a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable diluent orcarrier, for use in the treatment of cancer. In one embodiment, saidcancer is selected from the group consisting of colorectal cancer,glioblastoma, gastric cancer, ovarian cancer, diffuse large B-celllymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, headand neck squamous cell carcinoma, breast cancer, hepatocellularcarcinoma, small cell lung cancer and non-small cell lung cancer. In oneembodiment, said cancer is selected from the group consisting ofcolorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuselarge B-cell lymphoma, chronic lymphocytic leukaemia, head and necksquamous cell carcinoma and lung cancer. In one embodiment, said canceris colorectal cancer.

The compound of Formula (I) will normally be administered to awarm-blooded animal at a unit dose within the range 2.5-5000 mg/m² bodyarea of the animal, or approximately 0.05-100 mg/kg, and this normallyprovides a therapeutically-effective dose. A unit dose form such as atablet or capsule will usually contain, for example 0.1-250 mg of activeingredient. The daily dose will necessarily be varied depending upon thehost treated, the particular route of administration, any therapiesbeing co-administered, and the severity of the illness being treated.Accordingly the practitioner who is treating any particular patient maydetermine the optimum dosage.

EXAMPLES

The various embodiments are illustrated by the following Examples. Theinvention is not to be interpreted as being limited to the Examples.During the preparation of the Examples, generally:

-   -   i. Operations were carried out at ambient temperature/room        temperature, i.e. in the range of about 17° C. to 30° C. and        under atmospheric conditions unless otherwise stated;    -   ii. Evaporations were carried out by rotary evaporation or        utilising Genevac equipment in vacuo and work-up procedures were        carried out after removal of residual solids by filtration;    -   iii. Flash chromatography purifications were performed on an        automated Armen Glider Flash: Spot II Ultimate (Armen        Instrument, Saint-Ave, France) or automated Presearch combiflash        companions using prepacked Merck normal phase Si60 silica        cartridges (granulometry: 15-40 or 40-63 μm) obtained from        Merck, Darmstad, Germany, silicycle silica cartridges or        graceresolv silica cartridges;    -   iv. Preparative chromatography was performed on a Waters        instrument (600/2700 or 2525) fitted with a ZMD or ZQ ESCi mass        spectrometers and a Waters X-Terra or a Waters X-Bridge or a        Waters SunFire reverse-phase column (C-18, 5 microns silica, 19        mm or 50 mm diameter, 100 mm length, flow rate of 40 mL/minute)        using decreasingly polar mixtures of water (containing 1%        ammonia) and acetonitrile or decreasingly polar mixtures of        water (containing 0.1% formic acid) and acetonitrile as eluents.        Examples 2, 6-8, 13, 16, 18, 19-22, 27, 29, 34, 39, 59, 60, 70        and 71 were isolated directly from preparative HPLC solutions        containing formic acid. The material isolated therefore        comprises a certain amount of formic acid;    -   v. Yields, where present, are not necessarily the maximum        attainable;    -   vi. Structures of end-products of Formula (I) were confirmed by        nuclear magnetic resonance (NMR) spectroscopy, with NMR chemical        shift values measured on the delta scale. Proton magnetic        resonance spectra were determined using a Bruker advance 700        (700 MHz), Bruker Avance 500 (500 MHz), Bruker 400 (400 MHz) or        Bruker 300 (300 MHz) instrument; 19F NMR were determined at 282        MHz or 376 MHz; 13C NMR were determined at 75 MHz or 100 MHz;        measurements were taken at around 20-30° C. unless otherwise        specified; the following abbreviations have been used:        s=singlet; d=doublet; t=triplet; q=quartet; p=pentet/quintet;        m=multiplet; dd=doublet of doublets; ddd=doublet of doublet of        doublet; dt=doublet of triplets; td=triplet of doublets;        qd=quartet of doublets; bs=broad signal;    -   vii. End-products of Formula (I) were also characterised by mass        spectroscopy following liquid chromatography (LCMS); LCMS was        carried out using an Waters Alliance HT (2790 & 2795) fitted        with a Waters ZQ ESCi or ZMD ESCi mass spectrometer and an X        Bridge 5 μm C-18 column (2.1×50 mm) at a flow rate of 2.4        mL/min, using a solvent system of 95% A+5% C to 95% B+5% C over        4 minutes, where A=water, B=methanol, C=1:1 methanol:water        (containing 0.2% ammonium carbonate); or by using a Shimadzu        UFLC or UHPLC coupled with DAD detector, ELSD detector and 2020        EV mass spectrometer (or equivalent) fitted with a Phenomenex        Gemini-NX C18 3.0×50 mm, 3.0 μm column or equivalent (basic        conditions) or a Shim pack XR—ODS 3.0×50 mm, 2.2 μm column or        Waters BEH C18 2.1×50 mm, 1.7 μm column or equivalent using a        solvent system of 95% D+5% E to 95% E+5% D over 4 minutes, where        D=water (containing 0.05% TFA), E=Acetonitrile (containing 0.05%        TFA) (acidic conditions) or a solvent system of 90% F+10% G to        95% G+5% F over 4 minutes, where F=water (containing 6.5 mM        ammonium hydrogen carbonate and adjusted to pH10 by addition of        ammonia), G=Acetonitrile (basic conditions);    -   viii. Intermediates were not generally fully characterised and        purity was assessed by thin layer chromatographic, mass        spectral, HPLC and/or NMR analysis;    -   ix. X-ray powder diffraction spectra were determined (using a        Bruker D4 Analytical Instrument) by mounting a sample of the        crystalline material on a Bruker single silicon crystal (SSC)        wafer mount and spreading out the sample into a thin layer with        the aid of a microscope slide. The sample was spun at 30        revolutions per minute (to improve counting statistics) and        irradiated with X-rays generated by a copper long-fine focus        tube operated at 40 kV and 40 mA with a wavelength of 1.5418        angstroms. The collimated X-ray source was passed through an        automatic variable divergence slit set at V20 and the reflected        radiation directed through a 5.89 mm antiscatter slit and a 9.55        mm detector slit. The sample was exposed for 0.03 seconds per        0.00570° 2-theta increment (continuous scan mode) over the range        2 degrees to 40 degrees 2-theta in theta-theta mode. The running        time was 3 minutes and 36 seconds. The instrument was equipped        with a Position sensitive detector (Lynxeye). Control and data        capture was by means of a Dell Optiplex 686 NT 4.0 Workstation        operating with Diffrac+software;    -   x. Differential Scanning Calorimetry was performed on a TA        Instruments Q1000 DSC. Typically, less than 5 mg of material        contained in a standard aluminium pan fitted with a lid was        heated over the temperature range 25° C. to 300° C. at a        constant heating rate of 10° C. per minute. A purge gas using        nitrogen was used at a flow rate 50 ml per minute    -   xi. The following abbreviations have been used: h=hour(s);        r.t.=room temperature (˜17-30° C.); conc.=concentrated;        FCC=flash column chromatography using silica;        DCM=dichloromethane; DIPEA=diisopropylethylamine;        DMA=N,N-dimethylacetamide; DMF=N,N-dimethylformamide;        DMSO=dimethylsulfoxide; Et₂O=diethyl ether; EtOAc=ethyl acetate;        EtOH=ethanol; K₂CO₃=potassium carbonate; MeOH=methanol;        MeCN=acetonitrile; MTBE=Methyltertbutylether; MgSO₄=anhydrous        magnesium sulphate; Na₂SO₄=anhydrous sodium sulphate;        THF=tetrahydrofuran; sat.=saturated aqueous solution; and    -   xii. IUPAC names were generated using ‘SmiToSd’, a proprietary        program built around the OpenEye Lexichem toolkit        (http://www.eyesopen.com/lexichem-tk), or Canvas, a different        proprietary program. ‘SmiToSd’ was used to name Examples 1 to 22        and 25 to 42, and Canvas was used to name Examples 23, 24 and 43        to 71. ‘SmiToSd’ did not automatically recognise stereochemistry        of the 3-substituted cyclobut-1-yl group present in certain of        the Examples, so the names of these Examples were manually        edited to include the correct cyclobutyl stereochemistry.        Furthermore, as stated in the introduction, the compounds        comprise an imidazo[4,5-c]quinolin-2-one core. However, in        certain Examples the IUPAC name describes the core as an        imidazo[5,4-c]quinolin-2-one. The imidazo[4,5-c]quinolin-2-one        and imidazo[5,4-c]quinolin-2-one cores are nevertheless the        same, with the naming convention slightly different because of        the peripheral groups.

Example 18-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one

Sodium hydride (60% dispersion in mineral oil) (21.14 g, 528.56 mmol)was added portion-wise to 3-(dimethylamino)propan-1-ol (27.3 g, 264.27mmol) in DMF (500 mL) at 10° C. over a period of 20 minutes undernitrogen. The resulting mixture was stirred at r.t. for 1 h.8-(6-Fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one(50.0 g, 132.14 mmol) was added portion-wise to the reaction mixture at10° C. over a period of 20 minutes under nitrogen. The resulting mixturewas stirred at r.t. for 16 h. The reaction mixture was diluted withwater and the precipitate collected by filtration, washed with water(300 mL) and dried under vacuum. The dried solid was triturated withEtOAc (2 L) and filtered. The crude product was purified bycrystallisation from MeCN to afford the desired product (50.0 g, 82%) asa white solid. NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.90-2.04 (4H,m), 2.29 (6H, s), 2.49 (2H, t), 2.93-3.07 (2H, m), 3.56-3.67 (5H, m),4.10-4.30 (2H, m), 4.43 (2H, t), 5.10 (1H, t), 6.89 (1H, d), 7.80 (1H,d), 7.92 (1H, dd), 8.21 (1H, d), 8.40 (1H, s), 8.51 (1H, d), 8.71 (1H,s). Mass Spectrum: m/z (ES+)[M+H]+=462.3.

The title material (49.5 g, 107.25 mmol) was suspended in MeCN (300 mL)to give a freely stirring thick solution. This solution was allowed tostir at r.t. overnight giving a thinner solution. The material wasfiltered, washed with cold (0° C.) MeCN (200 mL) and dried overnight invacuo at 30° C. to give the title material in crystalline form A (48 g,97%) as a white solid. NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ1.81-1.99 (4H, m), 2.16 (6H, s), 2.37 (2H, t), 2.73 (2H, qd), 3.51 (3H,s), 3.59 (2H, t), 4.07 (2H, dd), 4.37 (2H, t), 5.14 (1H, ddd), 6.94-7.01(1H, m), 7.95 (1H, dd), 8.14 (1H, d), 8.18 (1H, dd), 8.43 (1H, s), 8.66(1H, d), 8.89 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=462.6.

The slurry filtrate and washings were combined and evaporated to recoveradditional title material (580 mg, 1.172%) as a pale cream solid. Thematerial obtained by the above procedure was determined to becrystalline form A and was analysed by XRPD to give an X-Raydiffractogram with the following characteristic peaks.

TABLE 1 Characteristic X-Ray powder diffraction peaks for Form A of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one Angle 2-Theta (2θ)Intensity (%) 3.9 100 11.6 78 21.3 32 22.2 28 10.7 25 7.7 21 15.4 2016.9 18 17.4 15 18.4 14

8-(6-Fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-onecan be prepared according to the following procedure.

Intermediate A1:8-(6-Fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one

Monopalladium(IV) disodium tetrachloride (0.975 g, 3.31 mmol) was addedto 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (60.0 g,165.64 mmol), (6-fluoropyridin-3-yl)boronic acid (25.7 g, 182.21 mmol),K₂CO₃ (68.7 g, 496.93 mmol) and3-(di-tert-butylphosphino)propane-1-sulfonic acid (0.445 g, 1.66 mmol)in 1,4-dioxane (400 mL) and water (100 mL) at r.t. under air. Theresulting mixture was stirred at 80° C. for 16 h. The reaction mixturewas diluted with water and the precipitate collected by filtration,washed with water (200 mL) and dried under vacuum. The resulting solidwas dissolved with DCM (18 L) and the mixture filtered through celite toremove Palladium residues. The solvent was removed under reducedpressure to afford the desired material (60.0 g, 96%) as a white solid,which was used without further purification. NMR Spectrum: ¹H NMR (400MHz, CDCl₃) δ 1.85-2.01 (2H, m), 2.86-3.02 (2H, m), 3.57-3.68 (5H, m),4.16-4.31 (2H, m), 5.11 (1H, t), 6.98-7.19 (1H, m), 7.83 (1H, dd), 8.16(1H, td), 8.30 (1H, dd), 8.50 (1H, s), 8.60 (1H, s), 8.77 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=379.2.

Intermediate A2:8-Bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one

A solution of sodium hydroxide (10.34 g, 258.48 mmol) in water (900 mL)was added to a stirred mixture of8-bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one (60.0 g, 172.32mmol), iodomethane (48.9 g, 344.63 mmol) and tetrabutylammonium bromide(5.55 g, 17.23 mmol) in DCM (1500 mL) at r.t. under air. The resultingmixture was stirred for 16 h then the DCM removed under reducedpressure. The precipitate was collected by filtration, washed with water(200 mL) and dried under vacuum to afford the desired material (58.0 g,93%) as a brown solid, which was used without further purification. NMRSpectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.81-1.98 (2H, m), 2.82-3.00 (2H,m), 3.60 (3H, s), 3.63 (2H, td), 4.05-4.35 (2H, m), 4.93 (1H, t), 7.69(1H, dd), 8.03 (1H, d), 8.36 (1H, s), 8.71 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=364.

On a larger scale, 8-bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one(1300 g, 3.73 mol) was charged to the vessel along withtetrabutylammonium bromide (130 g, 0.40 mol) and 2-MeTHF (20.8 L). Asolution of NaOH (240 g, 6.00 mol) in water (20.8 L) was then added over5 minutes with an observed exotherm from 18-24° C. The biphasic mixturewas heated to 42-48° C. before the addition of methyl iodide (465 mL,7.47 mol) as a solution in 2-MeTHF (930 mL). The reaction was stirred at45° C. for 17 h at which point HPLC analysis showed 2.9% startingmaterial and 97.1% product. The reaction mixture was combined with thatof the other large scale batches for concentration in vacuo. Theresulting aqueous suspension was then returned to the vessel andslurried for 1 h with the product material obtained from the developmentbatches combined at this point. The product was then isolated byfiltration, washing with water (2×12 L) before oven drying under vacuumat 40° C. In total 3479 g of8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one was isolated.Analytical data was consistent with that obtained from previous batches.

Intermediate A3: 8-Bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one

Triethylamine (143 mL, 1025.07 mmol) was added to6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic acid (120 g, 341.69mmol) in DMF (600 mL) at r.t. under air. The resulting mixture wasstirred for 30 minutes then diphenyl phosphorazidate (113 g, 410.03mmol) was added. The resulting mixture was stirred for 30 minutes atr.t. then at 60° C. for 2 h. The solvent was removed under reducedpressure and the reaction mixture diluted with water. The precipitatewas collected by filtration, washed with water (250 mL) and dried undervacuum to afford the desired material (120 g, 101%) as a brown solid,which was used without further purification.

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.72-1.95 (2H, m), 2.59-2.80(2H, m), 3.58 (2H, td), 3.98-4.11 (2H, m), 4.75-5.04 (1H, m), 7.75 (1H,dd), 7.97 (1H, d), 8.43 (1H, s), 8.71 (1H, s), 11.71 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=348.

On a larger scale, 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic acid(2011 g, (2005 g active), 5.71 mol) was added to the vessel with DMF(18.2 L). Triethylamine (4.7 L, 33.72 mol) was added with an endothermobserved from 21-18° C. Diphenyl phosphorazidate (1600 mL, 7.42 mol) wasadded over 10 minutes with an observed exotherm from 21° C. to 23° C.over the addition. The exotherm continued with the batch reaching 55° C.after 1 h (jacket held at 30° C.) with gas evolution. The reactioninitially went into solution with a precipitate then forming after ˜30minutes. Once the temperature had stabilised the batch was analysed byHPLC showing consumption of starting material and 99% product. The batchwas heated to 60° C. for h with HPLC again indicating consumption ofstarting material and 98% product. The batch was concentrated in vacuoto a minimum volume (˜3 volumes) and the residue added to water (17 L)rinsing in with a further portion of water (10 L). The mixture wasslurried for 1 h and filtered, washing with water (2×17 L). The solidwas then returned to the vessel and slurried in sat. NaHCO₃ solution (10L) and MeOH (495 mL) for 1 h. The solid was collected by filtration,washing with water (2×3.5 L) and then oven dried in vacuo at 40° C. for116 h to obtain 2023 g of desired material. Analytical data wasconsistent with that obtained from previous batches.

Intermediate A4: 6-Bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic acid

A solution of sodium hydroxide (79 g, 1977.60 mmol) in water (1500 mL)was added to a stirred mixture of ethyl6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylate (150 g, 395.52 mmol)in MeOH (1500 mL) at r.t. under air. The resulting mixture was stirredat 70° C. for 2 h then the solvent removed under reduced pressure. Thereaction mixture was adjusted to pH=3 with 2M hydrochloric acid. Theprecipitate was collected by filtration, washed with water (500 mL) anddried under vacuum to afford the desired material (120 g, 86%) as awhite solid, which was used without further purification. NMR Spectrum:¹H NMR (400 MHz, DMSO-d6) δ 1.75-1.82 (2H, m), 2.05-2.09 (2H, m),3.85-3.94 (5H, m), 7.95 (1H, d), 8.18 (1H, d), 8.65 (1H, s), 9.01 (1H,s). Mass Spectrum: m/z (ES+)[M+H]+=351.1.

On a larger scale, ethyl6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylate (1925 g, 5.08 mol) wascharged to the vessel with EtOH (12.5 L). 2M NaOH (12.5 L, 25.03 mol)was then added with an exotherm from 22-35° C. over the 20 minuteaddition. The batch was heated to 70-80° C. for 17 h at which point HPLCindicated 98.3% product and <1% starting material.

The batch was concentrated in vacuo to remove EtOH and returned to thevessel. A 2M HCl solution (13 L) was then added until pH 5-6 wasobtained maintaining a batch temperature below 50° C. An exotherm from20-32° C. was observed over the 40 minute addition. A precipitate formedwhich was slurried at 20-25° C. for 1.5 h before filtration, washingwith water until pH neutral (3×7 L). The collected solid was dried undervacuum at 70° C. to give 1794 g of desired material. Analytical data wasconsistent with that obtained from previous batches.

Intermediate A5: Ethyl 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylate

DIPEA (139 mL, 794.75 mmol) was added to ethyl6-bromo-4-chloroquinoline-3-carboxylate (100 g, 317.90 mmol) andtetrahydro-2H-pyran-4-amine (35.4 g, 349.69 mmol) in DMA (1000 mL) atr.t. under air. The resulting mixture was stirred at 60° C. for 16 hthen the solvent removed under reduced pressure. The mixture wasazeotroped twice with toluene to afford the desired material (150 g,124%) as a brown solid, which was used without further purification.

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.36 (3H, t), 1.58-1.75 (2H,m), 1.90-2.02 (2H, m), 3.40 (2H, t), 3.81-3.98 (2H, m), 3.98-4.19 (1H,m), 4.37 (2H, q), 7.82 (1H, d), 7.92 (1H, dd), 8.56 (1H, s), 8.86 (1H,s). Mass Spectrum: m/z (ES−)[M−H]−=378, 380.

On a larger scale, ethyl 6-bromo-4-chloroquinoline-3-carboxylate (2196g, (1976 g active), 6.28 mol) was charged to the vessel with DMA (16 L).Tetrahydro-2H-pyran-4-amine (1224 g, 12.10 mol) was added over 10minutes with an observed exotherm of 21-27° C. DIPEA (3.5 L, 20.09 mol)was added with no observed exotherm. The mixture was heated to 75-85° C.and the resulting solution stirred for 18.5 h at 80° C. HPLC indicatedconsumption of starting material and 99.2% product. The reaction wascooled to 50° C. and then poured into water (50 L). The resultingsuspension was stirred for 2 h at r.t. and the solids isolated byfiltration, washing with water (8 L then 2×4 L). The solid was driedunder vacuum at 40° C. for 55 h to give 2307 g of desired material.Analytical data was consistent with that obtained from previous batches.

Intermediate A6: Ethyl 6-bromo-4-chloroquinoline-3-carboxylate

DMF (0.119 mL, 1.54 mmol) was added to ethyl6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate (160 g,384.37 mmol) in thionyl chloride (800 mL) at r.t. under air. Theresulting mixture was stirred at 75° C. for 16 h then the solventremoved under reduced pressure. The resulting mixture was azeotropedtwice with toluene then n-hexane (500 mL) added. The precipitate wascollected by filtration, washed with n-hexane (200 mL) and dried undervacuum to afford the desired material (100 g, 83%) as a brown solid. NMRSpectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.47 (3H, t), 4.51 (2H, q), 7.95(1H, dd), 8.11 (1H, d), 8.60 (1H, d), 9.24 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=314, 316.

On a larger scale, ethyl6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate (5765g, 13.85 mol) was charged to the vessel with thionyl chloride (28.8 L).An exotherm from 20-26° C. was observed. DMF (4.4 mL) was added with noobserved exotherm and the batch heated to 75° C. and stirred for 17 h.HPLC showed 1.3% starting material remained with 98.0% product. Thereaction was concentrated in vacuo and the residue azeotroped withtoluene (25 L). The resulting solid was then slurried in heptane (18.5L) for 2.5 h, filtered and washed with heptane (3×4 L). The solid wasdried under vacuum at 35° C. to give 4077 g of the desired material (93%crude yield) which contained ˜5% of ethyl6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate inaddition to ˜4% hydrolysis product by HPLC (90% pure). The crudematerial (4077 g) was returned to the vessel and reprocessed withthionyl chloride (14.5 L) and DMF (2.2 mL). The mixture was heated to75° C. for 40 h. The thionyl chloride was removed in vacuo and theresidue azeotroped with toluene (10 L). The residue was slurried inheptane (18 L) for ˜16 h at 20° C. The solid was collected byfiltration, one portion being filtered under nitrogen and washed withheptane (3 L) to yield 2196 g of desired material (90% NMR assay, 99% byHPLC). The remainder of the batch was filtered under air and washed withheptane (3 L) to yield 1905 g of the desired material (88% NMR assay,99% by HPLC). The yellow solids were combined for further processing(4101 g, 3653 g active, 83% yield, 99% by HPLC).

Intermediate A7: Ethyl6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate

DBU (102 mL, 679.62 mmol) was added drop-wise to ethyl2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate(296.5 g, 679.62 mmol), in acetone (1.2 L) at r.t. over a period of 2minutes. The resulting solution was stirred for 16 h then the solidremoved by filtration and washed with MTBE to afford the desiredmaterial (180 g, 64%) as light yellow solid. NMR Spectrum: ¹H NMR (400MHz, DMSO-d6) δ 1.30 (3H, t), 3.71 (3H, s), 4.25 (2H, q), 5.60 (2H, s),6.90-6.95 (2H, m), 7.12-7.25 (2H, m), 7.67 (1H, d), 7.80-7.90 (1H, m),8.30 (1H, d), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=418.

On a larger scale, ethyl2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate(8434 g, (7730 g assumed active), 17.71 mol) was charged to the vesselwith acetone (23.2 L) at 15° C. DBU (2.8 L, 18.72 mol) was added over 25minutes with an observed exotherm from 18-23° C. over the addition. Aprecipitate formed after ˜25 minutes and the batch continued to exothermreaching a maximum of 37° C. after 1 h. The reaction was stirred at 20°C. for 16.5 h at which point HPLC indicated consumption of startingmaterial and 96.5% product. The resulting precipitate was collected byfiltration washing with TBME (4×3.4 L). The solid was then dried undervacuum at 40° C. to give 6033 g of the desired material as a white solid(81.6% yield over 3 steps, 99.8% purity by HPLC). Analytical data wasconsistent with that obtained on previous batches.

Intermediate A8: Ethyl2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate

(E)-Ethyl 3-(dimethylamino)acrylate (98 g, 685.00 mmol) was addedportion-wise to 5-bromo-2-fluorobenzoyl chloride (163 g, 685 mmol) andDIPEA (120 mL, 685.00 mmol) in toluene (800 mL) at 10° C. over a periodof 10 minutes. The resulting solution was stirred at 70° C. for 16 hthen allowed to cool. (4-Methoxyphenyl)methanamine (94 g, 685 mmol) wasadded to the mixture over a period of 20 minutes at r.t. The resultingsolution was stirred for 3 h then the reaction mixture diluted with DCM(4 L), and washed with water (3×1 L). The organic phase was dried overNa₂SO₄, filtered and evaporated to give the desired material (300 g,100%) as brown oil, which was used immediately in the subsequentreaction without further purification. Mass Spectrum: m/z(ES+)[M+H]+=436.

On a larger scale, 5-bromo-2-fluorobenzoyl chloride (4318 g, 4205 gactive, 17.71 mol) was charged to the vessel as a solution in toluene(7.5 L). DIPEA (3150 mL, 18.08 mol) was added with no observed exotherm.Ethyl-3-(dimethylamino)acrylate (2532 g, 17.71 mol) was addedportionwise over 30 minutes maintaining a batch temperature <40° C. Anexotherm from 21-24° C. was noted over the 30 minute addition with afurther slow rise to 38° C. over 1 h. The reaction was stirred at 20-30°C. for 16.5 h. 4-Methoxybenzylamine (2439 g, 17.78 mol) was addedportionwise over 30 mins maintaining a batch temperature <40° C. Anexotherm of 25-30° C. was observed over the addition with coolingprovided by a reduced jacket temperature of 15° C. The reaction wasstirred for 4 h at 20-30° C. after which HPLC indicated 93.2% of desiredmaterial. The batch was split for workup with each half of the mixturediluted with DCM (28.6 L) and washed with water (3×7.8 L). The organicswere dried over MgSO₄ (˜550 g) and filtered, washing with DCM (4 L). Thecombined organics were then concentrated to give 8444 g of the desiredmaterial as an oil (8434 g, 106% yield, 94.7% purity by HPLC).Analytical data was consistent with that obtained from previous batches.

Intermediate A9: 5-Bromo-2-fluorobenzoyl chloride

Thionyl chloride (75.0 mL, 1027.36 mmol) was added drop-wise to5-bromo-2-fluorobenzoic acid (150 g, 684.91 mmol), in toluene (1.2 L)and DMF (12 mL) at r.t. over a period of 1 h. The resulting mixture wasstirred at 70° C. for 16 h then the mixture allowed to cool andconcentrated in vacuo to afford the desired material (160 g, 98%) aslight yellow oil, which was used without further purification. NMRSpectrum: ¹H NMR (400 MHz, DMSO-d6) δ 7.26-7.31 (1H, m), 7.83 (1H, dd),8.02 (1H, d).

On a larger scale, 3-bromo-6-fluorobenzoic acid (3888 g, 17.75 mol) wascharged to the vessel at 20° C. followed by toluene (29.2 L). Thionylchloride (1950 ml, 26.88 mol) was added, followed by DMF (310 mL) withno observed exotherm. The mixture was heated to 65-75° C. (solutionobtained above ˜45° C.) with no observed exotherm and slight gasevolution. The reaction was stirred for 40 h at this temperature atwhich point HPLC analysis showed 87.6% product, 3.4% starting material.The reaction was concentrated in vacuo and azeotroped with toluene (18L) to give 4328 g of the desired material (103% yield, 87.3% by HPLC).

8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-onecan also be prepared directly from8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one in thefollowing manner:

8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one

Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[242′-amino-1,1′-biphenyl)]palladium(II)(0.070 g, 0.09 mmol) was added to8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (3.2 g, 8.83mmol), K₂CO₃ (3.66 g, 26.50 mmol) andN,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine(3.25 g, 10.60 mmol) in 1,4-dioxane (80 mL) and water (15 mL) undernitrogen. The resulting mixture was stirred at 90° C. for 2 h. Thereaction mixture was concentrated and diluted with EtOAc (500 mL) andwashed sequentially with water (2×100 mL), and sat. brine (100 mL). Theorganic layer was dried over Na₂SO₄, filtered and the volume reduced toapproximately 80 mL in vacuo. The precipitate was collected byfiltration, washed with Et₂O (10 mL) and dried under vacuum to affordthe desired material (2.80 g, 68.7%) as a white solid. Analytical dataconsistent with material synthesised by alternate route.

On a larger scale,8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (1700.1 g)was suspended in EtOH (20.4 L) in a 50 L vessel then K₂CO₃ (1948.7 g)andN,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine(1731.4 g) added. EtOH (6.8 L) and purified water (5.1 L) were added tothe mixture followed by the additionchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[242′-amino-1,1′-biphenyl)]palladium(II)(37.3 g). The mixture was heated to reflux (77-80° C.) and stirred for30 mins at reflux then cooled to 20° C. prior to being distilled underreduced pressure to a volume of 12.6 L. The batch was then cooled to15-25° C. and purified water (19.9 L) added. The batch was stirred for 1h 5 mins, filtered and the filter cake washed with purified water (3×3.7L) then dried under vacuum at 40° C. to afford crude desired material(1978 g, 91.3%). The reaction was repeated on a similar scale to delivera further 2084 g of crude material. The purification of the crude8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one(2066.9 g) was carried out in 6 portions of 350 g or less.

Crude8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one(350.1 g) was charged to a 10 L flask with EtOH (7.7 L) and heated untila solution was formed (68-73° C.). Activated charcoal (35 g) was addedand the solution stirred at 70-75° C. for 1 h. The hot solution wasfiltered using a porosity 3 sinter funnel through a celite pad (˜40 g)in small portions to ensure the product stayed in solution. The celitepad was washed with hot EtOH (2 L) to remove any residual product on thecelite and the initial filtrate charged to the vessel and the washfiltrate was stored in a carboy. This process was repeated with theremaining portions of crude material. After completion of the 6 hotfiltrations carried out over 2 days the filtrate in the vessel wasdistilled under reduced pressure until the remaining filtrate (held in acarboy) could be added. The batch was then heated until a solution wasformed (69° C.) and the distillation was then continued until the volumein the vessel was equal to 5 volumes of the input material (maximumdistillation batch temperature=55° C.). The distillation was stopped andthe batch cooled to 5-15° C., filtered, washed with EtOH (2.3 L) anddried to give the pure desired product (1926 g, 93.2% yield).

Analytical data consistent with material synthesised by alternateroutes/different scales.

Intermediate A3, 8-Bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-onecan also be prepared in the following manner:

Intermediate A3: 8-Bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one

1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (18.9 g, 81.9 mmol) wasadded portionwise to a mixture of6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxamide (57.3 g, 163.7 mmol)and DBU (54.7 g, 360.1 mmol) in MeOH (500 mL) at 0° C. The resultingmixture was allowed to warm and stirred at r.t. for 30 minutes. Theresulting mixture was evaporated to dryness and the residue trituratedwith a mixture of petroleum ether/EtOAc (5:1, 1000 mL) to afford thedesired material (46.0 g, 81%) as a yellow solid. NMR Spectrum: ¹H NMR(400 MHz, DMSO-d6) δ 1.55-1.64 (2H, m), 1.87-1.98 (2H, m), 3.28-3.42(2H, m), 3.79-3.89 (2H, m), 3.95-3.98 (1H, m), 7.62 (1H, bs), 7.70-7.85(2H, m), 7.89 (1H, d), 8.12 (1H, bs), 8.60 (1H, s), 8.71 (1H, s).

Intermediate A10: 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxamide

A mixture of 6-bromo-4-chloroquinoline-3-carboxamide (50 g, 175.4 mmol),tetrahydro-2H-pyran-4-amine (26.2 g, 193 mmol) and DIPEA (56.13 mL,438.5 mmol) in DMA (500 mL) was stirred at 90° C. overnight. The mixturewas allowed to cool and poured into water (1500 mL).

The precipitate was filtered, washed with water (2×200 mL) and driedunder reduced pressure to afford the desired material (57.3 g, 93%) as awhite solid. NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 2.88-1.92 (2H,m), 2.59-2.78 (2H, m), 3.50-3.62 (3H, m), 3.96-4.08 (2H, m), 4.92-4.98(1H, m), 7.80 (1H, m), 7.99 (1H, dd), 8.46 (1H, d), 8.74 (1H, s).

Intermediate A11: 6-Bromo-4-chloroquinoline-3-carboxamide

DMF (1.506 mL, 19.37 mmol) was added to6-bromo-4-oxo-1H-quinoline-3-carboxylic acid (51.93 g, 193.72 mmol) andthionyl chloride (353 mL, 4843.07 mmol) at r.t. and the resultingsolution stirred at 70° C. for 2 h under an inert atmosphere. Theresulting solution was evaporated to dryness and the residue azeotropedwith toluene to afford 6-bromo-4-chloroquinoline-3-carbonyl chloride(62.13 g). The 6-bromo-4-chloroquinoline-3-carbonyl chloride wasdissolved in DCM (420 mL) and added portionwise to ammonium hydroxide(251 mL, 1937.23 mmol) at 0° C. over 15 minutes. The organic solvent wasremoved under reduced pressure and the solid collected by filtration,washed with water, Et₂O and then dried to afford the desired material(52.8 g, 95%) as a white solid. NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6)δ 8.00-8.11 (3H, m), 8.24 (1H, s), 8.45 (1H, s), 8.92 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=287.

Intermediate A12: 6-Bromo-4-oxo-1H-quinoline-3-carboxylic acid

2N Sodium hydroxide (506 mL, 1011.43 mmol) was added to a stirredsuspension of ethyl 6-bromo-4-oxo-1H-quinoline-3-carboxylate (59.9 g,202.29 mmol) in EtOH (590 mL) and the resulting solution stirred at 75°C. for 1.5 h. Water was added and the mixture cooled to 0° C. The pH ofthe solution was adjusted to 3 using hydrochloric acid and theprecipitate collected by filtration. The solid was washed with water,EtOH/water (1:1) then Et₂O before being dried to afford the desiredmaterial (51.9 g, 96%) as a beige solid. NMR Spectrum: ¹H NMR (500 MHz,DMSO-d6) δ 7.80 (1H, d), 8.05 (1H, d), 8.37 (1H, s), 8.93 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=270.

Intermediate A13: Ethyl 6-bromo-4-oxo-1H-quinoline-3-carboxylate

Diphenyl ether (870 mL) was heated to 240° C. then diethyl2-[[(4-bromophenyl)amino]methylidene]propanedioate (75 g, 219.18 mmol)added portionwise. The mixture was stirred at 240° C. for 60 minutes ina flask fitted with dean-stark apparatus. After cooling (25° C.) acrystallized solid was formed. The mixture was diluted with Et₂O and thesolid was collected by filtration, washed with Et₂O and dried to affordthe desired material (59.9 g) as a beige crystallized solid, which wasused without purification or characterisation.

Intermediate A14: Diethyl2-[[(4-bromophenyl)amino]methylidene]propanedioate

Diethyl 2-(ethoxymethylene)malonate (71.5 mL, 354.02 mmol) was added to4-bromoaniline (42 g, 244.15 mmol) in EtOH (420 mL) and the resultingmixture stirred at 78° C. overnight. After cooling to 10° C. the whitesolid was collected by filtration, washed with heptane and dried toafford the desired material (75 g, 90%) as a white crystallized solid.NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.25 (6H, s), 4.10-4.27 (4H,m), 7.38 (2H, d), 7.57 (2H, d), 8.37 (1H, bs). Mass Spectrum: m/z(ES+)[M+H]+=344.

The preparation ofN,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amineis described below.

N,N-Dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine

Butyllithium (2.5N, 4.8 mL, 50.96 mmol) was added to a solution of3-(5-bromopyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (2.07 g, 7.99mmol) and 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane(2.79 g, 15.00 mmol) in THF (20 mL) at −78° C. over 10 minutes under aninert atmosphere. The resulting solution was stirred for 4 h at 18° C.The reaction was then quenched by the addition of a sat. aqueoussolution of ammonium chloride then partitioned between EtOAc (100 mL)and water (100 mL). The organic layer was concentrated in vacuo and theresidue purified by FCC, eluting with EtOAc/petroleum ether (1:3) toafford the desired material (270 mg, 11%) as a yellow solid. MassSpectrum: m/z (ES+)[M+H]+=225.

3-(5-Bromopyridin-2-yl)oxy-N,N-dimethylpropan-1-amine

3-(Dimethylamino)propan-1-ol (3.09 g, 29.95 mmol) was added to a mixtureof sodium hydride (2.4 g, 60.00 mmol) in DMF (50 mL) over a period of 20min at r.t. 5-Bromo-2-fluoropyridine (5.81 g, 33.01 mmol) was added andthe resulting solution stirred for 4 h at 30° C. The reaction was thenquenched by the addition of a sat. aqueous solution of ammonium chlorideand the resulting mixture concentrated under vacuum. The residue waspurified by FCC, eluting with DCM/MeOH in Et₂O (10:1) to afford thedesired material (5.2 g, 67%) as yellow oil. Mass Spectrum: m/z(ES+)[M+H]+=259.

Example 28-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one

Pd(Ph₃P)₄ (2.074 g, 1.79 mmol) was added to a mixture of8-bromo-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one(13 g, 35.89 mmol),N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine(13.15 g, 43.07 mmol) and cesium carbonate (23.39 g, 71.78 mmol) in1,4-dioxane (200 mL) and water (40 mL) under nitrogen. The resultingmixture was stirred at 90° C. for 3 h before being allowed to cool. Thereaction mixture was concentrated and diluted with EtOAc (750 mL), andwashed sequentially with water (2×150 mL), and sat. brine (150 mL). Theorganic layer was dried over Na₂SO₄, filtered and evaporated to affordcrude product. The crude product was purified by FCC, elution gradient 0to 10% MeOH in DCM, to afford the desired material (12.50 g, 75%) as awhite solid. NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.90 (2H, q),2.16 (6H, s), 2.37 (2H, t), 2.72-2.92 (2H, m), 3.01 (2H, d), 3.21 (3H,s), 3.50 (3H, s), 3.79-3.95 (1H, m), 4.37 (2H, t), 5.12 (1H, t), 6.97(1H, d), 7.82-7.98 (1H, m), 8.11 (1H, d), 8.19 (2H, dd), 8.42 (1H, s),8.67 (1H, d), 8.87 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=462.

Intermediate B1:8-Bromo-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one

Methyl iodide (11.49 mL, 183.81 mmol) was added to a mixture of8-bromo-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one (32g, 91.90 mmol), sodium hydroxide (5.51 g, 137.85 mmol) andtetrabutylammonium bromide (2.94 g, 9.19 mmol) in DCM (400 mL) and water(300 mL) and the resulting mixture stirred at r.t. for 12 h. The DCM wasremoved in vacuo and the precipitate collected by filtration, washedwith water (200 mL) and dried under vacuum to afford the desiredmaterial (25.00 g, 75%) as a pale yellow solid. NMR Spectrum: ¹H NMR(400 MHz, DMSO-d6) δ 2.72-2.86 (2H, m), 2.9-3.08 (2H, m), 3.22 (3H, s),3.49 (3H, s), 3.85-3.89 (1H, m), 4.88-5.06 (1H, m), 7.74 (1H, dd), 7.98(1H, d), 8.50 (1H, d), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=362,364.

Intermediate B2:8-Bromo-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one

Triethylamine (39.3 mL, 281.89 mmol) was added to6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylic acid(33 g, 93.96 mmol) in DMF (200 mL) at r.t. After stirring for 30 minutesdiphenyl phosphorazidate (28.4 g, 103.36 mmol) was added and theresulting mixture stirred at 60° C. for 2 h. The reaction mixture waspoured into water (500 mL), the precipitate collected by filtration,washed with water (200 mL) and dried under vacuum to afford the desiredmaterial (32.0 g, 98%) as a yellow solid, which was used without furtherpurification. NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 2.75-2.82 (2H,m), 2.9-3.05 (2H, m), 3.22 (3H, s), 3.80-3.90 (1H, m), 4.85-4.99 (1H,m), 7.71 (1H, dd), 7.94 (1H, d), 8.48 (1H, d), 8.69 (1H, s), 10.42 (1H,s). Mass Spectrum: m/z (ES+)[M+H]+=348, 350.

Intermediate B3:6-Bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylic acid

Sodium hydroxide (190 mL, 379.70 mmol) was added to ethyl6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylate (36 g,94.92 mmol) in a mixture of MeOH (120 mL) and THF (120 mL) and theresulting mixture stirred at 60° C. for 3 h. The solvent was removedunder reduced pressure and the mixture adjusted to pH 3 with 2Mhydrochloric acid. The precipitate was collected by filtration, washedwith water (300 mL) and dried under vacuum to afford the desiredmaterial (33.0 g, 99%) as a pale yellow solid, which was used withoutfurther purification. Mass Spectrum: m/z (ES+)[M+H]+=351.

Intermediate B4: Ethyl6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylate

DIPEA (41.6 mL, 238.43 mmol) was added to ethyl6-bromo-4-chloroquinoline-3-carboxylate (30 g, 95.37 mmol) and3-methoxycyclobutan-1-amine hydrochloride (15.75 g, 114.44 mmol) in DMA(100 mL) and the resulting mixture stirred at 75° C. for 5 h. Thesolvent was removed under reduced pressure to afford the desiredmaterial (36.0 g, 100%) as a yellow solid, which was used withoutfurther purification. NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.38(3H, t), 1.85-1.98 (2H, m), 2.75-7.89 (2H, m), 3.17 (3H, s), 3.65-3.78(1H, m), 3.98-4.05 (1H, m), 4.35 (2H, q), 7.60 (1H, d), 7.70 (1H, dd),8.40 (1H, d), 8.84-8.85 (1H, m). Mass Spectrum: m/z (ES+)[M+H]+=379.

Intermediate B2:8-Bromo-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one, canalso be prepared in the following manner.

DBU (5.36 mL, 35.86 mmol) was added in one portion to a mixture of6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxamide (6.28g, 17.93 mmol) and 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (1.667g, 7.17 mmol) in MeOH (65 mL). The resulting mixture was stirred at r.t.for 18 h. The resulting mixture was evaporated to dryness and theresidue was purified by FCC, elution gradient 0 to 10% MeOH in DCM, toafford the desired material (6.48 g, 104%). Data consistent withmaterial produced from alternate synthesis described earlier.

Intermediate B5:6-Bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxamide

DIPEA (13.76 mL, 78.80 mmol) was added to a mixture of6-bromo-4-chloroquinoline-3-carboxamide (7.5 g, 26.27 mmol) and3-methoxycyclobutan-1-amine hydrochloride (3.98 g, 28.89 mmol) in DMA(35 mL) and the resulting mixture stirred at 100° C. for 18 h. Thereaction mixture was diluted with water (250 mL) and the precipitate wascollected by filtration, washed with water (50 mL) and dried undervacuum to afford the desired material (6.28 g, 68.3%) as a tan solid,which was used without further purification. NMR Spectrum: ¹H NMR (400MHz, DMSO-d6) δ 2.45-2.55 (2H, m), 2.76-2.88 (2H, m), 3.17 (3H, s), 3.66(1H, q), 4-4.16 (1H, m), 7.67 (1H, s), 7.80 (1H, dd), 7.93 (1H, dd),8.15 (1H, s), 8.59 (1H, s), 8.69 (1H, s), 9.34 (1H, s). Mass Spectrum:m/z (ES+)[M+H]+=350, 352.

Example 38-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one

8-Bromo-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one(0.13 g, 0.33 mmol) was added toN,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine(0.121 g, 0.40 mmol), cesium carbonate (0.322 g, 0.99 mmol) andPd(Ph₃P)₄ (0.038 g, 0.03 mmol) in 1,4-dioxane (5 mL) and water (1 mL)under nitrogen. The resulting mixture was stirred at 80° C. for 2 h. Thecrude product was purified by preparative HPLC (Waters XBridge Prep C18OBD column, 5 μm silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 0.1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford the desired material (0.050 g, 30.8%) as a whitesolid. NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.82-2.10 (7H, m), 2.18(6H, s), 2.35-2.50 (2H, m), 3.0-3.1 (2H, m), 3.31-3.39 (2H, m), 3.35(3H, s), 3.61-3.74 (2H, m), 4.36 (2H, t), 6.99 (1H, d), 7.97 (1H, d),8.01 (1H, dt), 8.39 (1H, d), 8.45 (1H, d), 8.97 (1H, s). Mass Spectrum:m/z (ES+)[M+H]+=494.

The following compounds were synthesised in an analogous fashion usingthe appropriate boronic ester and the appropriate bromide:

Example Structure Name  4*

8-[6-(3-dimethylaminopropoxy)pyridin- 3-yl]-3-methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinolin-2-one methanesulfonic acid salt  5**

8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3- methylimidazo[4,5-c]quinolin-2-one 6

8-[6-(3-dimethylaminopropoxy)pyridin- 3-yl]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3- methylimidazo[4,5-c]quinolin-2-one  7

8-[6-(3-dimethylaminopropoxy)pyridin- 3-yl]-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one  8**

8-[6-(3-dimethylaminopropoxy)pyridin- 3-yl]-7-fluoro-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one  9**

8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxetan-3- yl)imidazo[5,4-c]quinolin-2-one10***

8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-3- yl]imidazo[5,4-c]quinolin-2-one11***

8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3S)-oxan-3- yl]imidazo[5,4-c]quinolin-2-one12**

8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3H- imidazo[4,5-c]quinolin-2-one13****

8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5- c]quinolin-2-one 14**

8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3- methylimidazo[4,5-c]quinolin-2-one15**

1-(cis-3-hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3- yl]imidazo[4,5-c]quinolin-2-one16*****

8-[6-(3-dimethylaminopropoxy)pyridin- 3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one 17*****

8-[6-(3-dimethylaminopropoxy)pyridin- 3-yl]-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one 18

8-[6-(3-dimethylaminopropoxy)-2- fluoropyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3- methylimidazo[4,5-c]quinolin-2-one 19

8-[6-(3-dimethylaminopropoxy)-2- fluoropyridin-3-yl]-7-fluoro-1-(cis-3-melhoxycyclobutyl)-3- mcthylimidazo[4,5-c]quinolin-2-one 20

8-[6-(3-dimethylaminopropoxy)-2- fluoropyridin-3-yl]-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one 21

8-[6-(3-dimethylaminopropoxy)-2- fluoropyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one 22

8-[6-(3-dimethylaminopropoxy)-2- fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one 23******

7-fluoro-3-methyl-8-[6-(3-pyrrolidin-1- ylpropoxy)-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5- c]quinolin-2-one 24******

7-fluoro-3-methyl-8-[6-(3-pyrrolidin-1- ylpropoxy)-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5- c]quinolin-2-one *Reaction stirred for18 h at 80° C. This compound can also be isolated as the methanesulfonicacid salt by dissolving the free base in DCM, treating withmethanesulfonic acid (~1.1 equiv), concentrating in vacuo andtriturating the residue with Et₂O. **Reaction stirred for 2 h at 90° C.***Reaction stirred for 75 mins at 120° C. ****The reaction usedstarting material tert-butyl8-bromo-1-(oxan-4-yl)-2-oxoimidazo[5,4-c]quinoline-3-carboxylate and wasstirred at 90° C for 2 h. The crude material was purified by prep HPLCusing decreasingly polar mixtures of water (containing 0.3% formic acid)and MeCN as eluents. No additional deprotection step was required.*****Reaction performed usingchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-bipheny1)]palladium(II)as the catalyst and stirred at 100° C for 3 h. ******Reaction stirredfor 1 h at 100° C.

Example 4

NMR Spectrum (free base): ¹H NMR (500 MHz, DMSO-d6) δ 1.90 (2H, p), 2.18(6H, s), 2.35-2.43 (2H, m), 3.55 (3H, s), 4.37 (2H, t), 5.07 (2H, dd),5.28 (2H, t), 6.13-6.24 (1H, m), 6.97 (1H, d), 7.98 (1H, dd), 8.15 (1H,d), 8.17-8.27 (1H, m), 8.50 (1H, d), 8.69 (1H, d), 8.94 (1H, s). NMRSpectrum (methanesulfonic acid salt): ¹H NMR (500 MHz, DMSO-d6) δ 2.06(2H, dt), 2.31 (3H, s), 2.59 (6H, s), 2.79-3.05 (2H, m), 3.55 (3H, s),4.40 (2H, t), 5.07 (2H, dd), 5.27 (2H, t), 6.14-6.24 (1H, m), 6.99 (1H,dd), 7.99 (1H, dd), 8.15 (1H, d), 8.25 (1H, dd), 8.53 (1H, d), 8.70 (1H,dd), 8.94 (1H, s), 9.35 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=433.6.

Example 5

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.87-1.92 (2H, m), 2.15 (6H,s), 2.38 (2H, t), 2.78-2.98 (4H, m), 3.50 (3H, s), 4.01-4.19 (1H, m),4.40 (2H, t), 4.92 (1H, p), 5.26 (1H, d), 6.97 (1H, d), 7.92 (1H, dd),8.11 (1H, d), 8.20 (1H, dd), 8.41 (1H, s), 8.67 (1H, d), 8.85 (1H, s).Mass Spectrum: m/z (ES+)[M+H]+=462.3.

Example 6

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.93 (2H, t), 2.22 (6H, s),2.48 (2H, t), 2.77-2.79 (2H, m), 2.93-3.02 (2H, m), 3.10 (3H, s), 3.49(3H, s), 3.69-3.9 (1H, m), 4.37 (2H, t), 5.06 (1H, p), 6.98 (1H, d),7.90 (1H, d), 8.04 (1H, dd), 8.37 (1H, d), 8.50 (1H, d), 8.91 (1H, s).Mass Spectrum: m/z (ES+)[M+H]+=480.

Example 7

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.92-1.98 (2H, m), 2.00 (3H,s), 2.01-2.07 (2H, m), 2.28 (6H, s), 2.50-2.54 (2H, m), 3.11 (2H, d),3.36 (2H, t), 4.35-4.38 (2H, m), 3.51 (3H, s), 4.36 (2H, t), 6.97 (1H,d), 7.90 (1H, dd), 8.11-8.15 (2H, m), 8.47 (1H, s), 8.57 (1H, d), 8.95(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=476.

Example 8

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.92-1.96 (4H, m), 2.23 (6H,s), 2.49-2.51 (2H, m), 2.62-2.75 (2H, m), 3.33-3.57 (5H, m), 4.05 (2H,dd), 4.37 (2H, t), 5.03-5.11 (1H, m), 6.98 (1H, d), 7.94 (1H, d), 8.08(1H, dd), 8.34 (1H, d), 8.54 (1H, s), 8.93 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=480.

Example 9

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.85-1.91 (2H, m), 2.16 (6H,s), 2.37 (2H, t), 3.53 (3H, s), 4.36 (2H, t), 5.01 (2H, t), 5.24 (2H,t), 6.13 (1H, p), 6.98 (1H, d), 7.93 (1H, d), 8.05 (1H, dd), 8.43 (1H,d), 8.50 (1H, s), 8.97 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=452.

Example 10

NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.78 (2H, dd), 1.90 (2H, p),2.17 (7H, s), 2.38 (2H, t), 2.66 (1H, qd), 3.38 (1H, td), 3.49 (3H, s),3.91 (1H, d), 4.12 (1H, dd), 4.21 (1H, t), 4.38 (2H, t), 4.91 (1H, ddd),7.01 (1H, d), 7.93 (1H, d), 8.06 (1H, dt), 8.26 (1H, d), 8.51 (1H, s),8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=479.

Example 11

NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.80 (2H, d), 1.90 (2H, p),2.17 (7H, s), 2.38 (2H, t), 2.61-2.73 (1H, m), 3.38 (1H, td), 3.50 (3H,s), 3.91 (1H, d), 4.12 (1H, dd), 4.21 (1H, t), 4.38 (2H, t), 4.86-4.98(1H, m), 7.01 (1H, d), 7.94 (1H, d), 8.06 (1H, dt), 8.27 (1H, d), 8.52(1H, s), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=479

Example 12

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.89-1.91 (2H, m), 2.15 (6H,s), 2.35 (2H, t), 2.78-2.83 (2H, m), 2.96-3.303 (2H, m), 3.19 (3H, s),3.83 (1H, p), 4.36 (2H, t), 5.09 (1H, p), 6.97 (1H, d), 7.91 (1H, dd),8.08 (1H, d), 8.20 (1H, dd), 8.43 (1H, d), 8.65 (1H, d), 8.87 (1H, s),11.54 (1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=448.

Example 13

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.85-1.92 (4H, m), 2.19 (6H,s), 2.40 (2H, t), 2.69-2.75 (2H, m), 3.57 (2H, t), 4.04-4.09 (2H, m),4.36 (2H, t), 5.08 (1H, p), 6.98 (1H, d), 7.94 (1H, dd), 8.10-8.21 (2H,m), 8.42 (1H, s), 8.65 (1H, s), 8.66 (1H, s), 11.57 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=448.

Example 14

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.77-1.90 (2H, m), 1.90-1.99(2H, m), 2.47-2.51 (2H, m), 2.72-2.91 (4H, m), 3.09 (4H, t), 3.50 (3H,s), 4.04-4.08 (1H, m), 4.33 (2H, t), 4.94 (1H, p), 5.24 (1H, d), 6.95(1H, d), 7.92 (1H, dd), 8.11 (1H, d), 8.20 (1H, dd), 8.41 (1H, d), 8.66(1H, d), 8.87 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=460.

Example 15

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.67-1.70 (4H, m), 1.88-1.97(2H, m), 2.44-2.51 (4H, m), 2.54-2.56 (2H, m), 2.79-2.95 (4H, m), 3.49(3H, s), 4.05-4.11 (1H, m), 4.37 (2H, t), 4.93 (1H, p), 5.24 (1H, d),6.96 (1H, d), 7.92 (1H, dd), 8.11 (1H, d), 8.20 (1H, dd), 8.40 (1H, d),8.66 (1H, d), 8.87 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=474.

Example 16

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.75-1.97 (4H, m), 2.10-2.22(1H, d), 2.24 (6H, s), 2.42-2.55 (2H, m), 2.62-2.77 (1H, m), 3.34-3.45(1H, m), 3.50 (3H, s), 3.92 (1H, d), 4.10-4.26 (2H, m), 4.35 (2H, t),4.89-5.02 (1H, m), 6.98 (1H, d), 7.92 (1H, dd), 8.12-8.19 (2H, m), 8.33(1H, s), 8.62 (1H, d), 8.89 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=462.25.

Example 17

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.75-1.97 (4H, m), 2.10-2.28(7H, m), 2.40 (2H, t), 2.62-2.77 (1H, m), 3.33-3.47 (1H, m), 3.50 (3H,s), 3.93 (1H, d), 4.10-4.26 (2H, m), 4.35 (2H, t), 4.91-5.05 (1H, m),6.98 (1H, d), 7.95 (1H, dd), 8.12-8.19 (1H, m), 8.35 (1H, s), 8.62 (1H,d), 8.89 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=462.25.

Example 18

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.85-2.00 (2H, m), 2.21 (6H,s), 2.46 (2H, t), 2.74-2.87 (2H, m), 2.91-3.07 (2H, m), 3.18 (3H,$),3.50 (3H, s), 3.75-3.89 (1H, m), 4.32 (2H, t), 4.91-5.08 (1H, m), 6.94(1H, d), 7.78 (1H, dd), 8.10 (1H, d), 8.16-8.27 (1H, m), 8.45 (1H, s),8.90 (1H, s); ¹⁹F NMR (300 MHz, DMSO-d6) δ 73.62. Mass Spectrum: m/z(ES+)[M+H]+=480.

Example 19

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.88-2.00 (2H, m), 2.23 (6H,s), 2.41-2.50 (2H, m), 2.71-2.83 (2H, m), 2.89-3.03 (1H, m), 3.15 (3H,s), 3.49 (3H, s), 3.71-3.86 (1H, m), 4.33 (2H, t), 4.91-5.08 (1H, m),6.97 (1H, d), 7.90 (1H, d), 8.12 (1H, dt), 8.43 (1H, dd), 8.92 (1H, s).¹⁹F NMR (300 MHz, DMSO-d6) δ 71.56 ppm, 116.913 ppm. Mass Spectrum: m/z(ES+)[M+H]+=498.

Example 20

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.79-1.90 (2H, m), 2.10-2.25(3H, m), 2.60-2.72 (1H, m), 2.73 (6H, s), 3.10-3.20 (2H, m), 3.30-3.47(4H, m), 3.91 (1H, d), 4.10 (1H, d), 4.28 (1H, t), 4.39 (2H, t),4.81-4.96 (1H, m), 6.99 (1H, d), 7.85 (1H, d), 8.14 (1H, d), 8.30 (1H,dd), 8.41 (1H, s), 8.91 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=480.

Example 21

NMR Spectrum: ¹H NMR (300 MHz, MeOD) δ 1.94-204 (2H, m), 2.20-2.30 (2H,m), 2.82 (6H, s), 2.82-3.00 (2H, m), 3.18-3.35 (2H, m), 3.62 (3H, s),3.62-3.71 (2H, m), 4.20 (2H, dd), 4.50 (2H, t), 5.12-5.25 (1H, m), 6.95(1H, d), 7.91 (1H, d), 8.19 (2H, m), 8.64 (1H, d), 8.87 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=480.

Example 22

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.75-1.99 (4H, m), 2.10-2.24(7H, m), 2.35-2.47 (2H, m), 2.55-2.69 (1H, m), 3.34-3.46 (1H, m), 3.92(1H, d), 4.03 (1H, d), 4.24-4.97 (3H, m), 4.81-4.99 (1H, m), 6.97 (1H,d), 7.84 (1H, d), 8.13 (1H, d), 8.24 (1H, dd), 8.40 (1H, s), 8.90 (1H,s). Mass Spectrum: m/z (ES+)[M+H]+=480.

Example 23

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.71 (4H, p), 1.78 (2H, d),1.95 (2H, p), 2.14 (1H, d), 2.53-2.74 (6H, m), 3.38 (2H, td), 3.49 (3H,s), 3.91 (1H, d), 4.12 (1H, dd), 4.21 (1H, t), 4.40 (2H, t), 4.91 (1H,t), 7.01 (1H, d), 7.94 (1H, d), 8.06 (1H, dt), 8.26 (1H, d), 8.51 (1H,s), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=506.

Example 24

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.64-1.74 (4H, m), 1.78 (2H,d), 1.94 (2H, p), 2.14 (1H, d), 2.46 (4H, d), 2.54-2.6 (1H, m),2.61-2.73 (1H, m), 3.34-3.43 (2H, m), 3.49 (3H, s), 3.91 (1H, d),4.07-4.17 (1H, m), 4.21 (1H, t), 4.40 (2H, t), 4.84-4.98 (1H, m),6.98-7.04 (1H, m), 7.93 (1H, d), 8.06 (1H, dt), 8.26 (1H, d), 8.51 (1H,s), 8.92 (1H, s); Mass Spectrum: m/z (ES+)[M+H]+=506.

The preparations for the bromo intermediates required for the synthesisof Examples 3-24 have either already been described or were carried outin the following manner by methylation of the corresponding3H-imidazo[4,5-c]quinolin-2-one intermediates.

Intermediate C1:8-Bromo-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one

A solution of sodium hydroxide (4 g, 100 mmol) in water (240 mL) wasadded to a solution of8-bromo-7-fluoro-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one(23 g, 62.81 mmol), methyl iodide (13.41 g, 94.48 mmol) andtetrabutylammonium bromide (2 g, 6.21 mmol) in DCM (400 mL) and theresulting solution stirred at r.t. overnight. The mixture wasconcentrated under vacuum and the solids collected by filtration. Thecrude product was re-crystallized from DCM:EtOAc in the ratio of 1:2 andthe solid dried in an oven under reduced pressure to afford the desiredmaterial (18 g, 75%) as an off-white solid. NMR Spectrum: ¹H NMR (300MHz, DMSO-d6) δ 2.70-2.85 (2H, m), 2.93-3.07 (2H, m), 3.22 (3H, s), 3.48(3H, s), 3.73-4.00 (1H, m), 4.86-5.15 (1H, m), 7.75-8.07 (1H, d),8.52-8.73 (1H, d), 8.93 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=380.

The following intermediates were prepared in an analogous fashion fromthe appropriate 3H-imidazo[4,5-c]quinolin-2-one intermediate:

Intermediate Structure Name Intermediate D1

8-bromo-3-methyl-1-[(3S)-oxan-3- yl]imidazo[5,4-c]quinolin-2-oneIntermediate E1*

8-bromo-3-methyl-1-[(3R)-oxan-3- yl]imidazo[5,4-c]quinolin-2-oneIntermediate F1

8-bromo-7-fluoro-3-methyl-1-(oxan- 4-yl)imidazo[5,4-c]quinolin-2-oneIntermediate G1

8-bromo-7-fluoro-3-methyl-1-(oxetan- 3-yl)imidazo[5,4-c]quinolin-2-oneIntermediate H1*

8-bromo-3-methyl-1-(oxetan-3- yl)imidazo[5,4-c]quinolin-2-oneIntermediate I1

8-bromo-7-fluoro-3-methyl-1-(4- methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one Intermediate J1

8-bromo-1-(cis-3- hydroxycyclobutyl)-3- methylimidazo[4,5-c]quinolin-2-one Intermediate K1**

8-bromo-7-fluoro-3-methyl-1-[(3S)- oxan-3-yl]imidazo[5,4-c]quinolin-2-one Intermediate L1

8-bromo-7-fluoro-3-methyl-1-[(3R)- oxan-3-yl]imidazo[5,4-c]quinolin-2-one *The reaction had not proceeded to completion so additional methyliodide, sodium hydroxide and tetrabutylammonium bromide were added andthe reaction stirred a further 16-18 h. **The reaction was stirred for72 h at ambient temperature.

Intermediate D1

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.82-1.88 (2H, m), 2.09-2.15(1H, m), 2.55-2.78 (1H, m), 3.30-3.47 (1H, m) 3.48 (3H, s), 3.92 (1H,d), 4.02-4.22 (2H, m), 4.68-4.88 (1H, m), 7.75 (1H, d), 7.99 (1H, d),8.35 (1H, s), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=362.2.

Intermediate E1

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.80-1.86 (2H, m), 2.07-2.12(1H, m), 2.61-2.75 (1H, m), 3.32-3.46 (1H, m), 3.47 (3H, s), 3.92-3.98(1H, m), 4.01-4.20 (2H, m), 4.72-4.83 (1H, m), 7.76 (1H, dd), 8.00 (1H,d), 8.34 (1H, d), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=362, 364.

Intermediate F1

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6, 100° C.) δ 1.88 (2H, d),2.59-2.84 (2H, m), 3.50 (3H, s), 3.60 (2H, t), 4.06 (2H, d), 4.95 (1H,s), 7.90 (1H, d), 8.56 (1H, d), 8.89 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=381.96.

Intermediate G1

Mass Spectrum: m/z (ES+)[M+H]+=352.

Intermediate H1

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 3.53 (3H, s), 5.01 (2H, dd),5.22 (2H, t), 6-6.18 (1H, m), 7.77 (1H, dd), 8.00 (1H, d), 8.51 (1H, d),8.97 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=334, 336.

Intermediate H

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6, 100° C.) δ 1.99 (3H, s),2.00-2.04 (2H, m), 2.98 (1H, d), 3.13-3.16 (1H, m), 3.32-3.38 (2H, m),3.53 (3H, s), 3.66-3.70 (2H, m), 7.99 (1H, d), 8.63 (1H, d), 9.00 (1H,s) Mass Spectrum: m/z (ES+)[M+H]+=394, 396.

Intermediate J1

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 2.65-2.72 (2H, m), 2.85-2.93(2H, m), 3.51 (3H, s), 4.02-4.09 (1H, m), 4.78 (1H, m), 5.26 (1H, d),7.73 (1H, dd), 7.97 (1H, d), 8.45 (1H, d), 8.92 (1H, s). Mass Spectrum:m/z (ES+)[M+H]+=348.

Intermediate K1

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.88-190 (2H, m), 2.09 (1H,d), 2.70 (1H, ddd), 3.36-3.44 (1H, m), 3.47 (3H, s), 3.94 (1H, d), 4.07(1H, dd), 4.15 (1H, t), 4.79 (1H, ddd), 7.97 (1H, d), 8.48 (1H, d), 8.93(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=380, 382.

Intermediate L1

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.86 (2H, dd), 2.11 (1H, d),2.69 (1H, ddd), 3.37-3.45 (1H, m), 3.48 (3H, s), 3.95 (1H, d), 4.08 (1H,dd), 4.18 (1H, t), 4.80 (1H, ddd), 7.98 (1H, d), 8.50 (1H, d), 8.94 (1H,s). Mass Spectrum: m/z (ES+)[M+H]+=380, 382.

Intermediate M1,8-bromo-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one, wasprepared in the following manner:

1,1-Dimethoxy-N,N-dimethylmethanamine (1.663 mL, 12.42 mmol) was addedto a stirred suspension of8-bromo-1-(4-methyloxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one (0.9 g,2.48 mmol) in DMF (8.28 mL) under an inert atmosphere and the reactionheated at 80° C. overnight. The reaction mixture was evaporated todryness and the crude product was dry-loaded onto silica and purified byFCC, elution gradient 2 to 10% MeOH in DCM, to afford the desiredmaterial (0.591 g, 63.2%) as a yellow solid. NMR Spectrum: ¹H NMR (400MHz, DMSO-d6) δ 1.92 (3H, s), 2.02 (2H, ddd), 2.95-3.03 (2H, m), 3.36(2H, td), 3.50 (3H, s), 3.68 (2H, dt), 7.72 (1H, dd), 8.00 (1H, d), 8.49(1H, d), 8.98 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=376.4.

The required 3H-imidazo[4,5-c]quinolin-2-one intermediates were preparedby cyclisation of the appropriate acid intermediate as follows:

Intermediate C2:8-Bromo-7-fluoro-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one

A solution of6-bromo-7-fluoro-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylicacid (5.90 g, 15.98 mmol), and triethylamine (9.72 g, 96.06 mmol) in DMF(100 mL) was stirred at ambient temperature for 2 h then diphenylphosphorazidate (11.02 g, 40.04 mmol) added The resulting solution wasstirred at 60° C. for 2 h before being concentrated in vacuo. Theresidue was diluted with water (80 mL) and the solids collected byfiltration and dried in an oven under reduced pressure to afford thedesired material (4.5 g, 77%) as a white solid. NMR Spectrum: ¹H NMR(300 MHz, CDCl₃) δ 2.75 (2H, m), 2.95 (2H, m), 3.25 (3H, s), 3.85 (1H,m), 4.75 (1H, m), 8.00 (1H, d), 8.62-8.58 (2H, t). Mass Spectrum: m/z(ES+)[M+H]+=366.

The following 3H-imidazo[4,5-c]quinolin-2-one intermediates wereprepared in a similar fashion from the appropriate carboxylic acidintermediates:

Intermediate Structure Name Intermediate D2*

8-bromo-1-[(3S)-oxan-3-yl]-3H- imidazo[4,5-c]quinolin-2-one IntermediateE2*

8-bromo-1-[(3R)-oxan-3-yl]-3H- imidazo[4,5-c]quinolin-2-one IntermediateF2

8-bromo-7-fluoro-1-(oxan-4-yl)-3H- imnidazo[4,5-c]quinolin-2-oneIntermediate G2*

8-bromo-7-fluoro-1-(oxetan-3-yl)-3H- imnidazo[4,5-c]quinolin-2-oneIntermediate J2*

8-bromo-1-(cis-3-hydroxycyclobutyl)- 3H-imidazo[4,5-c]quinolin-2-one*The reaction was stirred at 60° C. for 1 h.

Intermediate D2

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.84-2.11 (3H, m), 2.62-2.76(1H, m), 3.35-3.44 (1H, m), 3.92-4.22 (3H, m), 4.71-4.80 (1H, m), 7.76(1H, dd), 7.98 (2H, d), 8.32 (1H, dd), 8.71 (1H, s), 11.85 (1H, bs).Mass Spectrum: m/z (ES+)[M+H]+=350.

Intermediate E2

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.82-2.11 (3H, m), 2.61-2.75(1H, m), 3.34-3.43 (1H, m), 3.91-4.21 (3H, m), 4.69-4.78 (1H, m), 7.75(1H, dd), 7.99 (2H, d), 8.33 (1H, dd), 8.69 (1H, s), 11.70 (1H, bs).Mass Spectrum: m/z (ES+)[M+H]+=350.

Intermediate F2

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6, 100° C.) δ 1.88 (2H, dd), 2.71(2H, qd), 3.59 (2H, td), 4.06 (2H, dd), 4.92 (1H, tt), 7.92 (1H, d),8.57 (1H, d), 8.72 (1H, s), 11.43 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=367.92.

Intermediate G2

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 5.01 (2H, t), 5.20 (2H, t),6.08 (1H, m), 7.96 (1H, d), 8.70-8.73 (1H, m), 8.74 (1H, s), 11.80 (1H,bs). Mass Spectrum: m/z (ES+)[M+H]+=338.

Intermediate J2

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 2.70-2.76 (2H, m), 2.81-2.90(2H, m), 4.04-4.08 (1H, m), 4.75 (1H, p), 7.74 (1H, dd), 7.95 (1H, d),8.45 (1H, d), 8.68 (1H, s), 11.62 (1H, bs). Mass Spectrum: m/z(ES+)[M+H]+=334, 336.

The above acid intermediates were prepared from the corresponding esterintermediate as follows:

Intermediate C3:6-Bromo-7-fluoro-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylicacid

A solution of sodium hydroxide (8 g, 200 mmol) in water (100 mL) wasadded to a solution of ethyl6-bromo-7-fluoro-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylate(6.0 g, 15.10 mmol) in MeOH (300 mL) and the resulting solution stirredovernight at ambient temperature. The temperature was increased to 40°C. for a further 2 h. The pH value of the solution was adjusted to 5with 1.5M hydrochloric acid and the solids collected by filtration anddried in an oven under reduced pressure to afford the desired material(5.6 g) as a white solid which was used without further purification.NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.98-1.91 (2H, m), 2.88-2.84(2H, m), 3.17 (1H, s), 3.77-3.70 (1H, t), 4.22-4.19 (1H, t), 7.73 (1H,d), 8.44 (1H, d), 8.88 (1H, s), 13.27 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=369.

The following carboxylic acid intermediates were prepared in a similarfashion from the appropriate ester precursor:

Intermediate Structure Name Intermediate D3*

6-bromo-4-[[(3S)-oxan-3- yl]amino]quinoline-3-carboxylic acidIntermediate E3*

6-bromo-4-[[(3R)-oxan-3- yl]amino]quinoline-3-carboxylic acidIntermediate F3**

6-bromo-7-fluoro-4-(oxan-4- ylamino)quinoline-3-carboxylic acidIntermediate G3***

6-bromo-7-fluoro-4-(oxetan-3- ylamino)quinoline-3-carboxylic acidIntermediate J3*

6-bromo-4-[(cis-3- hydroxycyclobutyl)amino] quinoline-3-carboxylic acid*The reaction was stirred between 60-70° C. for 1-3 h. **The reactionwas stirred at ambient temperature overnight. ***The reaction wasperformed using a mixture of THF and water as the solvent and was heatedat 65° C. for 3 h.

Intermediate D3

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.50-1.57 (1H, m), 1.61-1.82(2H, m), 1.98-2.13 (1H, m), 3.48-3.72 (3H, m), 3.89 (1H, d), 4.15-4.26(1H, m), 7.77 (1H, dd), 7.95 (1H, d), 8.31 (1H, d), 8.90 (1H,$), 13.38(1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=351.

Intermediate E3

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.50-1.56 (1H, m), 1.62-1.83(2H, m), 1.99-2.12 (1H, m), 3.50-3.71 (3H, m), 3.89 (1H, d), 4.16-4.28(1H, m), 7.78 (1H, dd), 7.94 (1H, d), 8.30 (1H, d), 8.94 (1H,$), 13.50(1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=351.

Intermediate F3

Mass Spectrum: m/z (ES+)[M+H]+=369.

Intermediate G3

Mass Spectrum: m/z (ES+)[M+H]+=341.

Intermediate J3

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 2.03-2.07 (2H, m), 2.85-2.93(2H, m), 4.00-4.04 (1H, t), 4.21-4.35 (2H, m), 7.95 (1H, d), 8.16 (1H,dd), 8.58 (1H, s), 8.99 (1H, s), 11.02 (1H, bs). Mass Spectrum: m/z(ES+)[M+H]+=337, 339.

The above ester intermediates were prepared from the appropriate ethyl4-chloroquinoline-3-carboxylate intermediates as follows:

Intermediate C4: Ethyl6-bromo-7-fluoro-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylate

A solution of ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate(7.5 g, 22.55 mmol), 3-methoxycyclobutan-1-aminehydrochloride (3.41 g,24.78 mmol) and DIPEA (14.61 g, 113.04 mmol) in DMA (25 mL) was stirredat 85° C. for 3 h. The reaction mixture was cooled and the solidscollected by filtration, washed with water (3×20 mL) and dried in anoven under reduced pressure to afford the desired material (6.9 g, 77%)as a white solid which was used without further purification. NMRSpectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.44-1.41 (3H, t), 2.21-2.14 (2H,m), 3.05-2.98 (2H, m), 3.30 (3H, s), 3.94-3.75 (1H, m), 4.11-4.06 (1H,m), 4.43-4.37 (2H, d), 7.70 (1H, d), 8.29 (1H, d), 9.07 (1H, d), 9.69(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=397.

The following ester intermediates were prepared in an analogous fashionfrom the appropriate amine and either ethyl6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate or ethyl6-bromo-4-chloroquinoline-3-carboxylate:

Intermediate Structure Name Intermediate D4*

ethyl 6-bromo-4-[[(3S)-oxan-3- yl]amino]quinoline-3-carboxylateIntermediate E4*

ethyl 6-bromo-4-[[(3R)-oxan-3- yl]amino]quinoline-3-carboxylateIntermediate F4**

ethyl 6-bromo-7-fluoro-4-(oxan-4- ylamino)quinoline-3-carboxylateIntermediate G4**

ethyl 6-bromo-7-fluoro-4-(oxetan- 3-ylamino)quinoline-3- carboxylateIntermediate J4**

ethyl 6-bromo-4-[(cis-3- hydroxycyclobutyl)amino]quinoline-3-carboxylate *The reaction was stirred at 80° C. for 16 h.**The reaction was stirred at 90° C. for 1-3 h.

Intermediate D4

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.36 (3H, t), 1.70-1.74 (1H,m), 1.75-1.77 (2H, m), 2.03-2.05 (1H, m), 3.58-3.61 (3H, m), 3.80-3.85(1H, m), 4.01-4.03 (1H, m), 4.35 (2H, q), 7.80 (1H, d), 7.89 (1H, dd),8.58 (1H, s), 8.67 (1H, d), 8.93 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=380.8.

Intermediate E4 NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.50-1.56 (1H,m), 1.62-1.84 (2H, m), 1.99-2.13 (1H, m), 3.51-3.73 (3H, m), 3.89 (1H,d), 4.12-4.22 (1H, m), 7.77 (1H, d), 7.90 (1H, d), 8.31 (1H, s), 8.94(1H, s), 13.41 (1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=379 IntermediateF4

Mass Spectrum: m/z (ES+)[M+H]+=397.

Intermediate G4

Mass Spectrum: m/z (ES+)[M+H]+=369.

Intermediate J4

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.35 (3H, t), 1.91-1.95 (2H,m), 2.77-2.81 (2H, m), 3.91-3.95 (2H, m), 4.35 (2H, q), 5.28 (1H, d),7.78 (1H, d), 7.85 (1H, dd), 8.37 (1H, d), 8.85 (1H, s), 8.89 (1H, d).Mass Spectrum: m/z (ES+)[M+H]+=365, 367.

The preparation of ethyl 6-bromo-4-chloroquinoline-3-carboxylate hasbeen described earlier. The preparation of ethyl6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate is described below:

Intermediate C5: Ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate

Thionyl chloride (150 mL, 2.08 mol) was added to a solution of ethyl6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate (25 g, 79.59 mmol) inDMF (50 mL) and the solution stirred at 80° C. for 4 h. The mixture wasconcentrated under vacuum and quenched by the addition of ice/water. Thereaction mixture was extracted with DCM (8×100 mL), the organic extractscombined and the mixture adjusted to pH=7 by the addition of 1.5Mammonium hydrogen carbonate. The resulting mixture was washed with water(3×100 mL), the organics dried over Na₂SO₄ and concentrated in vacuo toafford the desired material (20 g, 76%) as a light yellow solid whichwas used without further purification.

NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.49-1.42 (3H, m), 4.54-4.82(2H, q), 7.86 (1H, d), 8.69 (1H, d), 9.23 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=334.

Intermediate C6: Ethyl 6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate

A solution of diethyl2-[[(4-bromo-3-fluorophenyl)amino]methylidene]propanedioate (90 g,249.88 mmol) in diphenyl ether (600 mL, 3.79 mol) was stirred at 240° C.for 2.5 h. The mixture was allowed to cool to 70° C., the solidscollected by filtration and dried in a vacuum oven to afford the desiredmaterial (50 g, 64%) as a white solid which was used without furtherpurification. NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6, (100° C.)) δ1.26-1.33 (3H, m), 4.25 (2H, q), 7.52 (1H, d), 8.37 (1H, d), 8.48 (1H,s), 12.05 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=314.

Intermediate C7: Diethyl2-[[(4-bromo-3-fluorophenyl)amino]methylidene]propanedioate

A solution of 4-bromo-3-fluoroaniline (56.6 g, 297.87 mmol) and1,3-diethyl 2-(ethoxymethylidene)propanedioate (72.45 g, 335.06 mmol) inEtOH (560 mL) was stirred at 80° C. for 4 h. The reaction mixture wasallowed to cool, the solids collected by filtration and dried in an ovento afford the desired material (90 g, 84%) as an off-white solid whichwas used without further purification. NMR Spectrum: ¹H NMR (400 MHz,DMSO-d6) δ 1.26 (6H, q), 4.14 (2H, q), 4.22 (2H, q), 7.18-7.25 (1H, m),7.57 (1H, dd), 7.64-7.7 (1H, m), 8.33 (1H, d), 10.62 (1H, d). MassSpectrum: m/z (ES+)[M+H]+=360.

The required 3H-imidazo[4,5-c]quinolin-2-one intermediates were preparedby cyclisation of the appropriate carboxamide intermediates as follows:

Intermediate H2: 8-Bromo-1-(oxetan-3-yl)-3H-imidazo[4,5-c]quinolin-2-one

DBU (2.34 mL, 15.64 mmol) was added to6-bromo-4-(oxetan-3-ylamino)quinoline-3-carboxamide (2.52 g, 7.82 mmol)and 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (0.727 g, 3.13 mmol)in MeOH (35 mL) and the resulting mixture stirred at ambient temperatureovernight. The mixture was evaporated to dryness and the residuepurified by FCC, elution gradient 0 to 20% MeOH in DCM, to afford thedesired material (0.485 g, 19.37%) as a cream solid. NMR Spectrum: ¹HNMR (400 MHz, DMSO-d6) δ 5.00 (2H, dd), 5.21 (2H, t), 5.87-6.15 (1H, m),7.75 (1H, dd), 7.97 (1H, d), 8.51 (1H, d), 8.72 (1H, s), 11.73 (1H, s).Mass Spectrum: m/z (ES+)[M+H]+=320, 322.

The following 3H-imidazo[4,5-c]quinolin-2-one intermediates wereprepared in an analogous fashion:

Intermediate Structure Name Intermediate K2 *

8-bromo-7-fluoro-1-[(3S)-oxan-3- yl]-3H-imidazo[4,5-c]quinolin-2- oneIntermediate L2

8-bromo-7-fluoro-1-[(3R)-oxan-3- yl]-3H-imidazo[4,5-c]quinolin-2- one*The reaction was stirred at ambient temperature for 70 h but was stillincomplete and so additional DBU and1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione and the mixture stirred atambient temperature for a further 3 h.

Intermediate K₂

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.77-1.93 (2H, m), 2.10 (1H,d), 2.68 (1H, qd), 3.34-3.44 (1H, m), 3.94 (1H, d), 4.08 (1H, dd), 4.18(1H, t), 4.75 (1H, ddd), 7.94 (1H, d), 8.48 (1H, d), 8.69 (1H, s), 11.63(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=366, 368.

Intermediate L2

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.7-1.93 (2H, m), 2.10 (1H,d), 2.63-2.75 (1H, m), 3.49-3.61 (1H, m), 3.84-4.03 (1H, m), 4.08 (1H,dd), 4.19 (1H, t), 4.76 (1H, t), 7.95 (1H, d), 8.49 (1H, d), 8.70 (1H,s), 11.66 (1H, s). m/z: ES+[M+H]+ 366, 368 Mass Spectrum: m/z(ES+)[M+H]+=366, 368.

The appropriate carboxamide intermediates were prepared as follows:

Intermediate H3: 6-Bromo-4-(oxetan-3-ylamino)quinoline-3-carboxamide

Oxetan-3-amine (0.614 g, 8.41 mmol) was added to6-bromo-4-chloroquinoline-3-carboxamide (2 g, 7.00 mmol) and DIPEA(2.440 mL, 14.01 mmol) in DMA (24 mL) and the resulting mixture stirredat 100° C. for 18 h. The crude product was purified by ion exchangechromatography, using an SCX column and eluting with 7M NH₃/MeOH, toafford the desired material (2.52 g, 112%) as a dark brown solid whichwas used without further purification. NMR Spectrum: ¹H NMR (400 MHz,DMSO-d6) δ 4.06-4.15 (2H, m), 4.16-4.20 (2H, m), 5.63-5.96 (1H, m),7.16-7.2 (3H, m), 7.22-7.26 (2H, m), 7.32 (1H, d), 7.93 (1H, d). MassSpectrum: m/z (ES+)[M+H]+=322, 324.

The following intermediates were prepared in an analogous fashion from6-bromo-4-chloro-7-fluoroquinoline-3-carboxamide:

Intermediate Structure Name Intermediate K3 *

6-bromo-7-fluoro-4-[[(3S)-oxan-3- yl]amino]quinoline-3-carboxamideIntermediate L3

6-bromo-7-fluoro-4-[[(3R)-oxan-3- yl]amino]quinoline-3-carboxamide *Thereaction was stirred at 80° C. overnight.

Intermediate K₃

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.52 (1H, td), 1.59-1.79 (2H,m), 2.02 (1H, d), 3.32-3.48 (2H, m), 3.68 (1H, dd), 3.87 (1H, dd),3.9-4.01 (1H, m), 7.56 (1H, s), 7.71 (1H, d), 8.10 (1H, s), 8.20 (1H,d), 8.62 (2H, d). Mass Spectrum: m/z (ES−)[M−H]−=366.

Intermediate L3

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.52 (1H, td), 1.67 (2H, ddd),2.02 (1H, d), 3.32-3.5 (2H, m), 3.68 (1H, dd), 3.87 (1H, dd), 3.91-4.02(1H, m), 7.56 (1H, s), 7.71 (1H, d), 8.10 (1H, s), 8.20 (1H, d), 8.62(2H, d). Mass Spectrum: m/z (ES+)[M+H]+=368, 370.

The preparation of 6-bromo-4-chloroquinoline-3-carboxamide has beendescribed earlier. The preparation of6-bromo-4-chloro-7-fluoroquinoline-3-carboxamide is described below.

Intermediate K4: 6-Bromo-4-chloro-7-fluoroquinoline-3-carboxamide

DMF (0.5 mL) was added to a stirred suspension of6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylic acid (22.5 g, 78.66mmol) in thionyl chloride (140 g, 1179.85 mmol) and the mixture heatedto reflux for 2 h. The reaction was allowed to cool, concentrated invacuo and the residue azeotroped twice with toluene to afford a yellowsolid. This solid was added portionwise to a solution of ammoniumhydroxide (147 mL, 1179.85 mmol) at 0° C. The white suspension wasstirred for 15 minutes then the solid filtered, washed with water anddried under vacuum to afford the desired material (23.80 g, 100%) as awhite powder.

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 8.92 (1H, s), 8.59 (1H, d),8.21 (1H, s), 8.09 (1H, d), 7.98 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=304.8.

Intermediate K5: 6-Bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylic acid

A solution of sodium hydroxide (18.34 g, 458.44 mmol) in water (100 mL)was added to a stirred suspension of ethyl6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate (28.8 g, 91.69 mmol)in EtOH (500 mL) at ambient temperature. The reaction mixture was thenstirred at 75° C. for 2 h, allowed to cool and the pH adjusted to 4using 2N hydrochloric acid. The precipitate was collected by filtration,washed with water and dried under vacuum to afford the desired material(23.30 g, 89%) as a white powder. NMR Spectrum: ¹H NMR (400 MHz,DMSO-d6) δ 14.78 (1H, s), 13.45 (1H, s), 8.93 (1H, s), 8.46 (1H, d),7.70 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=287.8.

The preparation of ethyl6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate has already beendescribed.

The required 3H-imidazo[4,5-c]quinolin-2-one intermediates were preparedby cyclisation of the appropriate amino intermediates as follows:

Intermediate 12:8-Bromo-7-fluoro-1-(4-methyloxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one

6-Bromo-7-fluoro-/V-(4-methyloxan-4-yl)quinoline-3,4-diamine (1.1 g,3.11 mmol) was added to bis(trichloromethyl)carbonate (0.553 g, 1.86mmol) in DCM (20 mL) and the resulting mixture stirred at 30° C. for 2h. The crude product was purified by FCC, elutiongradient 0 to 5% MeOHin DCM, to afford the desired material (0.950 g, 80%) as a brown solidwhich was used without further purification.

The following intermediate was prepared in an analogous fashion from theappropriate precursor:

Intermediate Structure Name Intermediate M2 *

8-bromo-1-(4-methyloxan-4-yl)- 3H-imidazo[4,5-c]quinolin-2-one*Triethylamine (1.2 equivalents) was added to the reaction mixture andthe reaction proceeded at ambient temperature over 2 h. The reactionmixture was purified using an SCX column with the desired materialeluted with 7M ammonia in MeOH.

Intermediate M2

Mass Spectrum: m/z (ES−)[M−H]−=362.39.

The preparation of the appropriate amino intermediates is describedbelow:

Intermediate 13:6-Bromo-7-fluoro-N′-(4-methyloxan-4-yl)quinoline-3,4-diamine

6-Bromo-7-fluoro-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine (1.215 g,3.16 mmol) was added to iron powder (1.8 g) in acetic acid (15 mL). Themixture was stirred and heated gently with a hot air gun (approximately60° C.) to initiate reaction. The heat source was removed and theresulting mixture was stirred for 1 h. The reaction mixture was dilutedwith water and the solids removed by filtration and discarded. Thefiltrate was concentrated in vacuo, diluted with water and extractedwith EtOAc. The organics were dried over Na₂SO₄ and concentrated invacuo to afford the desired material (1.10 g, 98%) as a brown solidwhich was used without further purification.

Intermediate 14:6-Bromo-7-fluoro-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine

6-Bromo-4-chloro-7-fluoro-3-nitroquinoline (1 g, 3.27 mmol) was added toa solution of 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (0.596g, 3.93 mmol) and DIPEA (1.715 mL, 9.82 mmol) in DMA (10 mL) and theresulting mixture stirred at 100° C. for 4 h. The reaction mixture wasdiluted with water and the solid collected by filtration and dried toafford the desired material (1.215 g, 97%) as a brown solid which wasused without further purification.

The synthesis of 6-bromo-4-chloro-7-fluoro-3-nitroquinoline has beenreported in the literature (e.g. Garcia-Echeverria, C. et al.,WO2006122806) and is available as a commercial reagent (e.g. AcesPharma, Inc—order number 74244).

6-Bromo-N-(4-methyloxan-4-yl)quinoline-3,4-diamine was prepared asfollows:

Intermediate M3: 6-Bromo-N′-(4-methyloxan-4-yl)quinoline-3,4-diamine

Water (8.35 mL) was added to a stirred mixture of6-bromo-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine (1.07 g, 2.92mmol), iron (0.979 g, 17.53 mmol) and ammonia hydrochloride (0.109 g,2.05 mmol) in EtOH (50.1 mL) and the resulting slurry heated to 105° C.for 2 h. The reaction was filtered warm through a pad of celite, washingwith MeOH, and the filtrate evaporated to dryness. The crude solid wasdissolved in DCM (10 mL) and washed with a sat. aqueous solution ofNaHCO₃ (10 mL) and sat. brine (10 mL). The organic layer was dried overMgSO₄, filtered and evaporated to afford the desired material (0.850 g,87%) as a pale orange solid. This was used without further purification.NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.19 (3H, s), 1.51 (2H, d),1.76 (2H, td), 3.43 (2H, td), 3.73 (2H, dt), 4.15 (1H, s), 5.45 (2H, s),7.39 (1H, dd), 7.67 (1H, d), 8.22 (1H, d), 8.51 (1H, s). Mass Spectrum:m/z (ES+)[M+H]+=336, 338.

Intermediate M4: 6-Bromo-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine

A solution of 6-bromo-4-chloro-3-nitroquinoline (1 g, 3.48 mmol),4-methyltetrahydro-2H-pyran-4-amine hydrochloride (1.055 g, 6.96 mmol)and triethylamine (1.939 mL, 13.91 mmol) in DMF (10 mL) was heated to100° C. for 1 h in a sealed tube in the microwave reactor. The mixturewas allowed to cool then poured into stirred water (50 mL) and theresulting yellow precipitate was collected by filtration and dried undervacuum to afford the desired material (1.070 g, 84%) as a yellow solid.This was used without further purification. NMR Spectrum: ¹H NMR (400MHz, DMSO-d6) δ 1.40 (3H, s), 1.78 (2H, dt), 1.89 (2H, ddd), 3.51-3.64(4H, m), 7.80 (1H, s), 7.91 (1H, d), 8.01 (1H, dd), 8.48 (1H, d), 9.18(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=366, 368.

The synthesis of 6-bromo-4-chloro-3-nitroquinoline has been reported inthe literature (e.g. Garcia-Echeverria, C. et al., WO2005054238) and isavailable as a commercial reagent (e.g. Aces Pharma, Inc—order number74381).

Intermediate N1, tert-butyl8-bromo-1-(oxan-4-yl)-2-oxoimidazo[5,4-c]quinoline-3-carboxylate, usedfor the preparation of example 13 was prepared as described below:

Intermediate N1: tert-Butyl8-bromo-1-(oxan-4-yl)-2-oxoimidazo[5,4-c]quinoline-3-carboxylate

Di-tert-butyl dicarbonate (376 mg, 1.72 mmol) was added to a mixture of8-bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one (300 mg, 0.86mmol) and triethylamine (0.240 mL, 1.72 mmol) in DCM (20 mL). Theresulting solution was stirred at ambient temperature for 4 h thenconcentrated in vacuo. The crude product was purified by FCC, elutiongradient 0 to 60% MeOH in DCM, to afford the desired material (310 mg,80%) as a white solid.

NMR Spectrum: ¹H NMR (300 MHz, CDCl₃) δ 1.72 (9H, s), 1.81-1.95 (2H, m),2.92-3.03 (2H, m), 3.57-3.65 (2H, m), 4.26 (2H, dd), 4.89-4.94 (1H, m),7.82 (1H d), 8.32-8.35 (1H, m), 8.39 (1H, s), 9.49 (1H, m). MassSpectrum: m/z (ES+)[M+H]+=448.

2-[3-(Azetidin-1-yl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine,2-(3-pyrrolidin-1-ylpropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineand3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy-N,N-dimethylpropan-1-aminewere prepared as follows:

2-[3-(Azetidin-1-yl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

n-Butyl lithium (4.65 mL, 11.62 mmol) was added to2-[3-(azetidin-1-yl)propoxy]-5-bromopyridine (2.1 g, 7.74 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.161 g, 11.62mmol) in THF (50 mL) at −78° C. over a period of 10 minutes and theresulting solution stirred at −78° C. for 1 h. The reaction was quenchedwith sat. Na₂SO₄ (10 mL) and the solvent removed in vacuo. The residuewas dissolved in DCM (100 mL), dried over Na₂SO₄, filtered andevaporated to afford the desired material (2.00 g, 81%) as a whitesolid. Mass Spectrum: m/z (ES+)[M+H]+=319.

2-[3-(Azetidin-1-yl)propoxy]-5-bromopyridine

Sodium hydride (1.364 g, 56.82 mmol) was added to3-(azetidin-1-yl)propan-1-ol (2.62 g, 22.73 mmol) in THF (20 mL) atambient temperature under an inert atmosphere and the reaction stirredfor 10 minutes. 5-Bromo-2-fluoropyridine (2.0 g, 11.36 mmol) was addedand the resulting solution stirred for 1 h before being quenched withwater (20 mL) and extracted with EtOAc (5×50 mL). The organics werecombined, dried over Na₂SO₄, filtered and concentrated in vacuo toafford the desired material (3.75 g, 122%) as a white solid. NMRSpectrum: ¹H NMR (300 MHz, CDCl₃) δ 1.80 (2H, m), 2.11 (2H, m), 2.55(2H, t), 3.18 (4H, t), 4.328 (2H, t), 6.64 (1H, d), 7.62 (1H, dd), 8.16(1H, d). Mass Spectrum: m/z (ES+)[M+H]+=271.

3-(Azetidin-1-yl)propan-1-ol

A solution of lithium aluminium hydride (2.0 M in THF) (8.38 mL, 16.76mmol) diluted in further THF (20 mL) was added to a mixture of methyl3-(azetidin-1-yl)propanoate (2 g, 13.97 mmol) in THF (5 mL) dropwise at0° C. under an inert atmosphere. The resulting solution was stirred at0° C. for 1 h then the reaction mixture treated with sodium sulphatedecahydrate and stirred for 30 minutes. The solid was removed byfiltration and discarded and the filtrate evaporated to afford thedesired material (1.240 g, 77%) as a colourless oil.

NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.51-1.57 (2H, m), 2-2.07 (2H,m), 2.6-2.66 (2H, m), 3.20 (4H, t), 3.7-3.76 (2H, m).

Methyl 3-(azetidin-1-yl)propanoate

Methyl acrylate (2.082 mL, 23.12 mmol) was added to a solution ofazetidine (1.2 g, 21.02 mmol) in DCM and the resulting solution stirredat ambient temperature, under an inert atmosphere for 16 h. The reactionmixture was evaporated and the crude product purified by FCC, elutedwith 25% EtOAc in DCM, to afford the desired material (2.0 g, 66.5%) asa colourless oil. NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.97-2.1 (2H,m), 2.33 (2H, d), 2.67 (2H, d), 3.18 (4H, t), 3.67 (3H, s).

2-(3-Pyrrolidin-1-ylpropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

n-Butyllithium (5.68 mL, 14.20 mmol) was added dropwise to a mixture of5-bromo-2-(3-pyrrolidin-1-ylpropoxy)pyridine (2.7 g, 9.47 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.64 g, 14.20mmol) in THF (20 mL) at −78° C. over a period of 10 minutes under aninert atmosphere. The resulting mixture was allowed to warm to ambienttemperature and stirred for 12 h. The reaction mixture was quenched bythe addition of a sat. aqueous solution of ammonium chloride, extractedwith EtOAc (2×50 mL) and the organic layer dried over Na₂SO₄, filteredand evaporated to afford the desired material (3.10 g, 99%) as a yellowoil. The product was used in the next step directly without furtherpurification. NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.26-1.41 (12H,m), 1.77-1.80 (4H, m), 1.95-2.04 (2H, m), 2.50-2.58 (4H, m), 2.62 (2H,t), 4.37 (2H, t), 6.69 (1H, d), 7.91 (1H, d), 8.52 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=251.

5-bromo-2-(3-pyrrolidin-1-ylpropoxy)pyridine

Sodium hydride (0.591 g, 14.77 mmol) was added portionwise to a solutionof 3-(pyrrolidin-1-yl)propan-1-ol (1.615 g, 12.50 mmol) in THF (20 mL)at to 0° C. then stirred at ambient temperature for 30 minutes.5-Bromo-2-fluoropyridine (2 g, 11.36 mmol) was added and the resultingmixture stirred at ambient temperature for 2 h before being quenched bythe addition of a sat. aqueous solution of ammonium chloride. Themoisture was extracted with EtOAc (2×100 mL), the organic layer driedover Na₂SO₄, filtered and evaporated to afford pale yellow solid. Thecrude product was purified by FCC, elution gradient 0 to 10% MeOH inDCM, to afford the desired material (2.70 g, 83%) as a yellow solid.

Mass Spectrum: m/z (ES+)[M+H]+=285.

3-[6-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy-N,N-dimethylpropan-1-amine

A solution of n-butyllithium (0.693 g, 10.83 mmol) in n-hexane (4.33 mL)was added to a stirred mixture of3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (2 g,7.22 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.014 g, 10.83 mmol) in THF (20 mL) at −78° C. over a period of 20minutes under an inert atmosphere. The resulting mixture was allowed towarm to ambient temperature and stirred for 2 h. The reaction mixturewas quenched with sat. NaHCO₃ solution and concentrated in vacuo. Thecrude product was purified by FCC, elution gradient 0 to 10% MeOH inDCM, to afford the desired material (2.50 g, 107%). Mass Spectrum: m/z(ES+)[M+H]+=325.

3-(5-Bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine

(E)-Diisopropyl diazene-1,2-dicarboxylate (15.80 g, 78.13 mmol) wasadded dropwise to 3-(dimethylamino)propan-1-ol (8.06 g, 78.13 mmol),5-bromo-6-fluoropyridin-2-ol (10 g, 52.09 mmol) and triphenylphosphine(20.49 g, 78.13 mmol) in DCM (150 mL) cooled to 0-5° C. under an inertatmosphere. The resulting solution was stirred at ambient temperaturefor 16 h then the solvent removed under reduced pressure. The residuewas diluted with EtOAc (50 mL) and the solid removed by filtration anddiscarded. The filtrate was acidified with hydrogen chloride in dioxane.The solid was collected by filtration then dissolved in a sat. aqueoussolution of Na₂CO₃ (200 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with water, brine, dried over Na₂SO₄and concentrated in vacuo to afford the desired material (9.00 g,62.3%). NMR Spectrum: ¹H NMR (300 MHz, CDCl₃) δ 1.89-1.98 (2H, m), 2.26(6H, s), 2.34 (2H, t), 4.30 (2H, t), 6.53 (1H, d), 7.74 (1H, t). MassSpectrum: m/z (ES+)[M+H]+=277.

5-Bromo-6-fluoropyridin-2-ol

A solution of sodium nitrite (21.67 g, 314.13 mmol) in water (150 mL)was added dropwise to a stirred mixture of5-bromo-6-fluoropyridin-2-amine (50 g, 261.78 mmol) and sulphuric acid(1.2 mL, 22.51 mmol) in water (750 mL) at 0-5° C. The resultingsuspension was stirred for 48 h at ambient temperature then theprecipitate collected by filtration, washed with water (200 mL) anddried under vacuum to afford the desired material (40.0 g, 80%) as apale yellow solid, which was used without further purification. NMRSpectrum: ¹H NMR (300 MHz, DMSO-d6) δ 6.55 (1H, d), 8.00 (1H, t), 11.71(1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=192.

5-bromo-6-fluoropyridin-2-amine

NBS (50.0 g, 280.99 mmol) was added slowly to 6-fluoropyridin-2-amine(30 g, 267.61 mmol) in MeCN (300 mL) cooled to 10-20° C. over a periodof 30 minutes. The resulting solution was stirred at ambient temperaturefor 60 minutes then the solvent removed under reduced pressure. Theresidue was diluted with water, the precipitate collected by filtration,washed with water (200 mL) and dried under vacuum to afford the desiredmaterial (50.0 g, 98%) as a white solid, which was used without furtherpurification. NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 6.29 (1H, d),6.57 (2H, bs), 7.65 (1H, t). Mass Spectrum: m/z (ES+)[M+H]+=191.

Examples 25 & 268-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-oneand8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one

Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(26.1 mg, 0.03 mmol) was added to8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one(1:1 mixture) (250 mg, 0.66 mmol),N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine(244 mg, 0.80 mmol) and Cs₂CO₃ (433 mg, 1.33 mmol) in 1,4-dioxane (20mL) and water (5 mL) and the resulting mixture stirred at 100° C. for 2h. The reaction mixture was poured into water (25 mL), extracted withDCM (2×50 mL), the organic layer dried over Na₂SO₄, filtered andevaporated to afford yellow residue. The crude product was purified bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.1% Formic acid) and MeCN as eluents. Fractions containingthe desired compound were evaporated to dryness to afford the desiredmaterial as a racemic mixture (175 mg, 53.3%) as a white solid.Optimisation on the Agilent 1100, AD column, (20 micron μm silica, 4.6mm diameter, 250 mm length) showed that MeCN/MeOH/TEA, 95/05/0.1 wouldgive the best separation. This method was used for the preparative HPLCpurification. The racemic mixture (130 mg, 0.27 mmol) was dissolved inEtOH (10 mL) and separated using preparative HPLC on AD column (20 μmsilica, 50 mm diameter, 250 mm length), two injections were required inorder to prep the entire sample. Mixed fractions were subjected to asecond separation using the above method and fractions containing thedesired pure enantiomers were evaporated to afford the desiredmaterials. This method gave mixed fractions which were repurified usingthe same conditions. Fractions containing the separated isomers wereevaporated to dryness:

Example 25: Isomer 1 (58 mg)

NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.87-1.98 (1H, m), 2.04 (3H,dt), 2.33 (8H, s), 2.47-2.64 (3H, m), 2.72 (1H, ddd), 3.36 (3H, s), 3.59(3H, s), 4.09-4.21 (1H, m), 4.43 (2H, t), 5.59 (1H, q), 6.88 (1H, d),7.80 (1H, dd), 7.92 (1H, dd), 8.22 (1H, d), 8.33 (1H, d), 8.50 (1H, d),8.70 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=476.

Example 26: Isomer 2 (58 mg)

NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.94 (1H, m), 1.99-2.11 (3H, m),2.32 (8H, s), 2.46-2.64 (3H, m), 2.66-2.83 (2H, m), 3.36 (3H, s), 3.59(3H, s), 4.17 (1H, m), 4.43 (2H, t), 5.44-5.72 (1H, m), 6.88 (1H, d),7.80 (1H, dd), 7.91 (1H, dd), 8.22 (1H, d), 8.33 (1H, d), 8.50 (1H, d),8.70 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=476.

The preparation of8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one(1:1 mixture) is described below:

Intermediate O1:8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one(1:1 Mixture)

A mixture of6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylicacid:6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylicacid (1:1 mixture) (13 g, 35.8 mmol), tetrabutylammonium bromide (1.16g, 3.60 mmol), iodomethane (7.645 g, 53.86 mmol) and sodium hydroxide(2.15 g, 53.75 mmol) in DCM (600 mL) and water (380 mL) was stirred atambient temperature overnight. The resulting solution was concentratedunder vacuum to remove the organics and the solids collected byfiltration, washed with water (5×10 mL) and dried in a vacuum oven toafford the desired material (racemic mixture) (9.8 g, 73%) as aoff-white solid. NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.81-1.87(1H, m), 2.33-2.51 (4H, m), 2.45-2.51 (1H, m), 3.28 (3H, s), 3.49 (3H,s), 4.02-4.21 (1H, m), 5.40 (1H, p), 7.73 (1H, dd), 7.98 (1H, d), 8.35(1H, d), 8.91 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=375.9.

Intermediate O2:8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one(1:1 Mixture)

A mixture of6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylicacid:6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylicacid (1:1 mixture) (17 g, 46.54 mmol), triethylamine (14.1 g, 139.34mmol) in DMF (270 mL) was stirred at ambient temperature for 1 h.Diphenyl phosphorazidate (25.6 g, 93.02 mmol) was added dropwise withstirring and the solution stirred at ambient temperature for a further20 minutes before being heated to 60° C. for 1 h. The reaction wasallowed to cool and concentrated under vacuum. The residue was dilutedwith water (300 mL), the solids collected by filtration and dried in anoven under reduced pressure to afford the desired material (as a racemicmixture) (13 g, 77%) as a off-white solid. Mass Spectrum: m/z(ES+)[M+H]+=362.2.

Intermediate O3:6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylicacid:6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylicacid (1:1 Mixture)

2N Sodium hydroxide (150 mL) was added to a mixture of ethyl6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate:ethyl6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate(1:1 mixture) (18.6 g, 47.2 mmol) in MeOH (500 mL) and water (100 mL)and the resulting solution stirred for 15 h at ambient temperature. Themixture was concentrated under vacuum and the residue diluted with water(300 mL). The pH value of the solution was adjusted to 5 with 2Nhydrochloric acid, the solids collected by filtration and dried in anoven under reduced pressure to afford the desired material (as a racemicmixture) (17.1 g) as a off-white solid. NMR Spectrum: ¹H NMR (400 MHz,DMSO-d6) δ 1.60-1.71 (2H, m), 1.81-1.88 (1H, m), 1.96-2.02 (1H, m),2.03-2.10 (2H, m), 3.21 (3H, s), 3.91-3.96 (1H, m), 4.51-4.72 (1H, m),7.77 (1H, d), 7.93 (1H, d), 8.45 (1H, d), 8.85 (1H, s), 13.30 (1H, bs).Mass Spectrum: m/z (ES+)[M+H]+=365.2.

Intermediate O4: Ethyl6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate:ethyl6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate(1:1 Mixture)

A mixture of ethyl 6-bromo-4-chloroquinoline-3-carboxylate (15 g, 47.69mmol), (trans)-3-methoxycyclopentan-1-amine (racemic mixture) (8.09 g,26.68 mmol) and DIPEA (19.68 g, 152.27 mmol) in DMA (100 mL) was stirredat 80° C. for 4 h under an inert atmosphere. The reaction was quenchedby the addition of water (500 mL), the solids collected by filtrationand dried in an oven under reduced pressure to afford the desiredmaterial (as a racemic mixture) (18.6 g) as a light brown solid. MassSpectrum: m/z (ES+)[M+H]+=393, 395.

The preparation of ethyl 6-bromo-4-chloroquinoline-3-carboxylate hasbeen described earlier.

Example 277-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one

3-(Pyrrolidin-1-yl)propan-1-ol (46.9 mg, 0.36 mmol) was added to sodiumhydride (29.1 mg, 1.21 mmol) in THF (4 mL) at ambient temperature over aperiod of 20 minutes.7-Fluoro-8-(6-fluoropyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one(120 mg, 0.30 mmol) was added. The resulting mixture was stirred atambient temperature for 2 h. The reaction mixture was quenched withwater and the crude product purified by FCC, elution gradient 0 to 5%MeOH in DCM. The crude product was purified by preparative HPLC (WatersXBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length),using decreasingly polar mixtures of water (containing 0.1% formic acid)and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford the desired material (60.0 mg, 38.7%) asa off-white solid. NMR Spectrum: ¹H NMR (300 MHz, MeOD) δ 1.90-2.00 (4H,m), 2.10-2.20 (2H, m), 2.81-3.00 (8H, m), 3.04-3.17 (2H, m), 3.28 (3H,s), 3.6 (3H, s), 3.85-3.96 (1H, m), 4.48 (2H, t), 5.00-5.13 (1H, m),6.88 (1H, d), 7.82 (1H, d), 8.05 (1H, d), 8.43-8.50 (2H, m), 8.83 (1H,s)

Mass Spectrum: m/z (ES+)[M+H]+=506.

The following compounds were prepared in an analogous fashion using theappropriate alcohol and the appropriate pyridyl fluoro intermediate.

Example Structure Name 28*

l-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one 29

3-methyl-1-[(3S)-oxan-3-yl]-8-[6-(3- pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one 30

3-methyl-1-(oxan-4-yl)-8-[6-(3- pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one 31

3-methyl-1-[(3S)-oxan-3-yl]-8-[6- (3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one 32

3-methyl-1-[(3R)-oxan-3-yl]-8-[6- (3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one 33*

1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin- 3-yl]imidazo[4,5-c]quinolin-2-one34

8-[6-[3-(azetidin-1-yl)propoxy]pyridin- 3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one 35**

1-(cis-3-methoxycyclobutyl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]- 3H-imidazo[4,5-c]quinolin-2-one36*

1-(oxan-4-yl)-8-[6-(3-piperidin-1- ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5-c]quinolin-2-one 37**

3-methyl-1-(oxan-4-yl)-8-[6-(3- piperidin-1-ylpropoxy)pyridin-3-yl]imidazo[5,4-c]quinolin-2-one 38**

8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3- methylimidazo[4,5-c]quinolin-2-one39*

8-[6-[3-(azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo- [5,4-c]quinolin-2-one *The reactionwas performed in DMF between 0° C. and ambient temperature. **Thereaction was performed in DMA at 50° C.

Example 28

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.67-1.96 (6H, m), 2.44-2.55(6H, m), 2.78-3.03 (4H, m), 3.19 (3H, s), 3.50 (3H, s), 3.84-3.88 (1H,m), 4.38 (2H, t), 5.13 (1H, p), 6.97 (1H, d), 7.92 (1H, dd), 8.12 (1H,dd), 8.20 (1H, dd), 8.43 (1H, s), 8.67 (1H, d), 8.88 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=488.

Example 29

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.68-1.86 (6H, m), 1.95 (2H,p), 2.10-2.19 (1H, d), 2.51-2.75 (7H, m), 3.35-3.49 (1H, m), 3.50 (3H,s), 3.92 (1H, d), 4.08-4.18 (1H, m), 4.22 (1H, t), 4.38 (2H, t),4.90-5.03 (1H, m), 6.98 (1H, d), 7.92 (1H, dd), 8.15-8.20 (1H, m), 8.25(1H, s), 8.32 (1H, s), 8.66 (1H, d), 8.90 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=488.

Example 30

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.67-1.73 (4H, m), 1.90-1.98(4H, m), 2.39-2.46 (4H, m), 2.54-2.61 (2H, m), 2.72 (2H, ddd), 3.52 (3H,s), 3.59 (2H, t), 4.06 (2H, dd), 4.38 (2H, t), 5.13-5.16 (1H, m), 6.98(1H, d), 7.96 (1H, dd), 8.14 (1H, d), 8.20 (1H, dd), 8.45 (1H, s), 8.67(1H, d), 8.91 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=488.

Example 31

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.38-1.50 (6H, m), 1.83-1.95(4H, m), 2.13-2.18 (1H, m), 2.35-2.43 (6H, m), 2.62-2.75 (1H, m),3.38-3.44 (1H, m), 3.49 (3H, s), 3.94 (1H, d), 4.13-4.27 (2H, m), 4.35(2H, t), 4.90-5.02 (1H, m), 6.99 (1H, d), 7.94 (1H, d), 8.13-8.18 (2H,m), 8.34 (1H, s), 8.48 (1H, d), 8.90 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=502.

Example 32

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.35-1.58 (6H, m), 1.85-1.98(4H, m), 2.12-2.21 (1H, m), 2.21-2.50 (6H, m), 2.60-2.80 (1H, m),3.33-3.48 (1H, m), 3.48 (3H, s), 3.89-3.97 (1H, m), 4.10-4.28 (2H, m),4.30-4.38 (2H, m), 4.90-5.08 (1H, m), 6.98 (1H, d), 7.93-8.0 (1H, m),8.13-8.22 (2H, m), 8.35 (1H, s), 8.63 (1H, s), 8.94 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=502.3.

Example 33

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.32-1.45 (2H, m), 1.45-1.51(4H, m), 1.88-1.98 (2H, m), 2.31-2.51 (6H, m), 2.81-2.83 (2H, m),2.97-3.11 (2H, m), 3.19 (3H, s), 3.50 (3H, s), 3.84-3.91 (1H, m), 4.36(2H, t), 5.10-5.17 (1H, m), 6.97 (1H, d), 7.93 (1H, d), 8.12 (1H, d),8.21 (1H, dd), 8.43 (1H, s), 8.68 (1H, d), 8.89 (1H, s). Mass Spectrum:m/z (ES+)[M+H]+=502.

Example 34

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.78-1.85 (4H, m), 2.05-2.18(3H, m), 2.66-2.80 (3H, m), 3.36-3.49 (8H, m), 3.94 (1H, d), 4.12-4.35(2H, m), 4.38 (2H, t), 4.94-4.98 (1H, m), 7.00 (1H, d), 7.92 (1H, d),8.13-8.20 (2H, m), 8.33 (1H, s), 8.63 (1H, s), 8.90 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=474.3.

Example 35

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.64-1.75 (4H, m), 1.94 (2H,p), 2.45 (3H, d), 2.53-2.58 (3H, m), 2.75-2.88 (2H, m), 2.94-3.08 (2H,m), 3.21 (3H, s), 3.87 (1H, p), 4.39 (2H, t), 5.08 (1H, p), 6.97 (1H,d), 7.90 (1H, dd), 8.09 (1H, d), 8.19 (1H, dd), 8.43 (1H, d), 8.65 (1H,s), 8.67 (1H, d), 11.50 (1H, s). m/z: ES+[M+H]+ 474. Mass Spectrum: m/z(ES+)[M+H]+=474.

Example 36

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.38 (2H, d), 1.46-1.53 (4H,m), 1.85-1.92 (4H, m), 2.27-2.42 (6H, m), 2.67-2.80 (2H, m), 3.52 (2H,t), 4.08 (2H, dd), 4.33 (2H, t), 5.10 (1H, p), 6.97 (1H, d), 7.93 (1H,d), 8.09 (1H, d), 8.12 (1H, d), 8.20 (1H, dd), 8.42 (1H, s), 8.65 (1H,s). Mass Spectrum: m/z (ES+)[M+H]+=488.

Example 37

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.40 (2H, d), 1.50 (4H, q),1.92 (4H, dq), 2.3-2.45 (6H, m), 2.66-2.8 (2H, m), 3.52 (3H, s), 3.59(2H, t), 4.07 (2H, dd), 4.37 (2H, t), 5.09-5.2 (1H, m), 6.96-6.99 (1H,d), 7.96 (1H, dd), 8.15 (1H, d), 8.18-8.21 (1H, m), 8.44 (1H, s), 8.66(1H, d), 8.90 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=502.46.

Example 38

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.74 (2H, p), 1.96 (2H, p),2.47 (2H, t), 2.78-2.87 (2H, m), 3.01 (2H, qd), 3.10 (4H, t), 3.21 (3H,s), 3.51 (3H, s), 3.87 (1H, p), 4.35 (2H, t), 5.08-5.18 (1H, m),6.93-6.97 (1H, d), 7.92 (1H, dd), 8.12 (1H, d), 8.18-8.21 (1H, d), 8.43(1H, d), 8.65-8.68 (1H, m), 8.88 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=474.43.

Example 39

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.74-1.78 (2H, m), 1.81-1.93(2H, m), 2.00-2.09 (2H, m), 2.65-2.77 (4H, m), 3.31-3.36 (4H, m), 3.51(3H, s), 3.58 (2H, t), 4.04-4.09 (2H, m), 4.34 (2H, t), 5.14 (1H, p),6.97 (1H, d), 7.94 (1H, dd), 8.13 (1H, d), 8.20 (1H, dd), 8.22 (1H, s),8.66 (1H, d), 8.90 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=474.

The required fluoro intermediates for Examples 27-39 have either alreadybeen described or were prepared from the appropriate bromo intermediatesas described below:

Intermediate P:8-(6-fluoropyridin-3-yl)-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one

Pd(Ph₃P)₄ (0.160 g, 0.14 mmol) was added to8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one (1 g,2.76 mmol), (6-fluoropyridin-3-yl)boronic acid (0.506 g, 3.59 mmol) andCs₂CO₃ (1.799 g, 5.52 mmol) in 1,4-dioxane (23 mL) and water (3 mL)under nitrogen. The resulting mixture was stirred at 100° C. for 3 hthen allowed to cool and the solvent removed under reduced pressure. Thecrude product was purified by FCC, elution gradient 0 to 7% MeOH in DCMto give the desired material (0.905 g, 87%) as a yellow solid. NMRSpectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.83-1.86 (2H, m), 2.15-2.19 (1H,m), 2.49-2.64 (1H, m), 3.38-3.41 (1H, m), 3.49 (3H, s), 3.93 (1H, d),4.15-4.26 (2H, m), 4.91-5.10 (1H, m), 7.42 (1H, dd), 7.96 (1H, dd), 8.13(1H, d), 8.38 (1H,$), 8.44 (1H, td), 8.72 (1H, d), 8.96 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=379.1.

The following fluoro intermediates were prepared in an analogous fashionfrom (6-fluoropyridin-3-yl)boronic acid and the appropriate bromointermediates, the synthesis of which has already been described:

Intermediate Structure Name Intermediate Q

8-(6-fluoropyridin-3-yl)-3-methyl- 1-[(3R)-oxan-3-yl]imidazo[5,4-c]-quinolin-2-one Intermediate R *

7-fluoro-8-(6-fluoropyridin-3-yl)- 1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2- one Intermediate S **

8-(6-fluoropyridin-3-yl)-1-(cis-3- methoxycyclobutyl)-3-methyl-imidazo[4,5-c]quinolin-2-one Intermediate T **

8-(6-fluoropyridin-3-yl)-1-(oxan- 4-yl)-3H-imidazo[4,5-c]quinolin- 2-oneIntermediate U ***

8-(6-fluoropyridin-3-yl)-1-(cis-3- methoxycyclobutyl)-3H-imidazo-[4,5-c]quinolin-2-one *The reaction was stirred at 80° C. for 2 h. **Thereaction was performed usingchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)as the catalyst and was stirred at 90° C. for 2 h. ***The reaction wasperformed with a 1:2 mixture of sodium tetrachloropalladate and3-(di-tert-butylphosphino)propane-1-sulfonic acid (0.05 M in water) asthe catalyst and ligand and K₂CO₃ as the base. The reaction was stirredat 80° C. for 3 h.

Intermediate Q

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.80-1.83 (2H, m), 2.15-2.18(1H, m), 2.49-2.73 (1H, m), 3.37-3.41 (1H, m), 3.49 (3H, s), 3.93 (1H,d), 4.16-4.26 (2H, m), 4.90-5.10 (1H, m), 7.42 (1H, dd), 7.97 (1H, dd),8.14 (1H, d), 8.38 (1H,$), 8.45 (1H, td), 8.71 (1H, d), 8.95 (1H, s).Mass Spectrum: m/z (ES+)[M+H]+=379.

Intermediate R

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 2.76-2.81 (2H, m), 2.91-3.05(2H, m), 3.13 (3H, s), 3.49 (3H, s), 3.78-3.82 (1H, m), 5.07-5.10 (1H,m), 7.40 (1H, dd), 7.94 (1H, d), 8.32 (1H, td), 8.45 (d) 8.59 (1H, s),8.95 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=397.

Intermediate S

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 2.83 (2H, s), 3.01 (2H, d),3.20 (3H, s), 3.51 (3H, s), 3.86 (1H, s), 5.07-5.18 (1H, m), 7.37 (1H,d), 7.96 (1H, d), 8.16 (1H, d), 8.49 (2H, d), 8.75 (1H, s), 8.92 (1H,s). Mass Spectrum: m/z (ES+)[M+H]+=379.

Intermediate T

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.90-1.96 (2H, m), 2.65-2.79(2H, s), 3.65 (2H, t), 4.01-4.11 (2H, m), 5.06-5.14 (1H, m), 7.40 (1H,dd), 8.02 (1H, dd), 8.15 (1H, d), 8.44-8.50 (2H, m), 8.71 (1H, s), 8.75(1H, dd), 11.75 (1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=365.

Intermediate U

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 2.71-2.84 (3H, m), 2.97-3.09(2H, m), 3.20 (3H, s), 3.86 (1H, p), 5.09 (1H, ddd), 7.35 (1H, dd), 7.83(1H, dd), 8.07 (1H, d), 8.42-8.5 (2H, m), 8.63 (1H, s), 8.73 (1H, d).Mass Spectrum: m/z (ES+)[M+H]+=365, 367.

Example 403-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one

Sodium hydride (50.7 mg, 2.11 mmol) was added to tert-butyl(3-hydroxypropyl)(methyl)carbamate (200 mg, 1.06 mmol) in DMF (5 mL) atambient temperature under air. The resulting solution was stirred for 1h then8-(6-fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one(200 mg, 0.53 mmol) was added and the resulting solution stirred atambient temperature overnight. The reaction mixture was quenched withwater (20 mL), extracted with EtOAc (5×20 mL), the organic layerscombined and washed with water (3×50 mL). The organic layer was driedover Na₂SO₄, filtered and evaporated to afford a white solid (262 mg,91%). This material was dissolved in DCM (10 mL) and TFA (5 mL, 64.90mmol) added. The reaction was stirred at ambient temperature for 1 hthen the solvent removed in vacuo. The crude product was purified bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5 μm silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.1% NH₄HCO₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford the desiredmaterial (60.0 mg, 27.7%) as a white solid. NMR Spectrum: ¹H NMR (300MHz, DMSO-d6) δ 1.86-1.94 (4H, m), 2.30 (3H, s), 3.08 (2H, t), 2.71 (2H,dd), 3.52 (3H, s), 3.58 (2H, t), 4.05 (2H, dd), 4.36 (2H, t), 5.15 (1H,p), 6.98 (1H, d), 7.94 (1H, dd), 8.12 (1H, d), 8.20 (1H, dd), 8.42 (1H,s), 8.65 (1H, d), 8.90 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=448.

The following compounds were prepared in an analogous fashion fromtert-butyl (3-hydroxypropyl)(methyl)carbamate and the appropriate fluorointermediate.

Example Structure Name 41

3-methyl-8-[6-(3-methylaminopropoxy)-pyridin-3-yl]-1-[(3S)-oxan-3-yl]imidazo- [5,4-c]quinolin-2-one 42

1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-methylaminopropoxy)pyridin-3- yl]imidazo[4,5-c]quinolin-2-one 43*

3-methyl-8-[6-[3-(methylamino)propoxy]-3-pyridyl]-1-[(3R)-tetrahydropyran-3- yl]imidazo[4,5-c]quinolin-2-one*The initial deprotonation and displacement reaction was performed inTHF.

Example 41

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.79-1.84 (2H, m), 2.06-2.21(3H, m), 2.67 (3H, s), 2.68-2.80 (1H, m), 3.10 (2H, t), 3.40-3.60 (5H,m), 3.94 (1H, d), 4.12-4.25 (2H, m), 4.43 (2H, t), 5.20 (1H, p), 7.08(1H, d), 8.10 (1H, d), 8.19-8.28 (1H, m), 8.40 (1H, s), 8.68 (1H, s),9.06 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=448.2.

Example 42

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.82-1.92 (2H, m), 2.29 (3H,s), 2.62 (2H, t), 2.77-2.88 (2H, m), 3.00 (2H, q), 3.21 (3H, s), 3.50(3H, s), 3.87 (1H, p), 4.38 (2H, t), 5.10 (1H, p), 6.98 (1H, d), 7.91(1H, d), 8.10 (1H, d), 8.21 (1H, dd), 8.42 (1H, s), 8.67 (1H, s), 8.89(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=448.

Example 43

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.84 (2H, m), 2.10 (3H, m),2.70 (4H, m), 3.10 (2H, m), 3.40 (1H, m), 3.50 (3H, s), 3.92 (1H, d),4.18 (2H, m), 4.43 (2H, t), 5.02 (1H, bs), 7.03 (1H, d), 8.03-9.01 (6H,m). Mass Spectrum: m/z (ES+)[M+H]+=448.2.

The preparation of the required fluoro intermediates for examples 40-43have already been described.

Example 448-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-onemethanesulfonic acid salt

N,N-Dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine(106 mg, 0.34 mmol), 2M K₂CO₃ (0.718 mL, 1.44 mmol) and8-bromo-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one(100 mg, 0.29 mmol) were suspended in dioxane (3 mL) and then degassedwith nitrogen. To this suspension was addeddichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (18.72mg, 0.03 mmol) and the resulting suspension heated in a sealed microwavevial at 80° C. for 1 h. The reaction was partitioned between water andDCM and the organic layer concentrated under reduced pressure. The crudeproduct was purified by FCC, elution gradient 0 to 10% methanolicammonia in DCM, to afford the desired compound (90 mg). The desiredmaterial can be isolated as a methanesulfonic acid salt by dissolvingthe isolated material in DCM (10 mL) then adding 1M methanesulfonic acidin DCM (0.201 mL, 0.20 mmol) and stirring the mixture at roomtemperature for 1 h. The solvent was removed in vacuo and the solid wastriturated in Et₂O to afford the methanesulfonic acid salt as a beigesolid (64.0 mg). NMR Spectrum (methanesulfonic acid salt): ¹H NMR (500MHz, DMSO-d6) δ 2.08-2.24 (2H, m), 2.31 (3H, s), 2.33-2.46 (1H, m), 2.54(1H, s), 2.83 (6H, s), 3.18-3.29 (2H, m), 3.55 (3H, s), 3.91 (1H, td),4.09-4.23 (2H, m), 4.27 (1H, td), 4.42 (2H, t), 5.79-5.9 (1H, m), 7.00(1H, dd), 7.98 (1H, dd), 8.16 (1H, d), 8.26 (1H, dd), 8.61 (1H, d), 8.71(1H, dd), 8.94 (1H, s), 9.34 (1H, s).

Mass Spectrum: m/z (ES+)[M+H]+=448.

The following compounds were prepared in an analogous fashion from theappropriate bromo intermediate.

Example Structure Name 45

8-[6-[3-(dimethylamino)propoxy]- 3-pyridyl]-3-methyl-1-[(3S)-tetra-hydrofuran-3-yl]imidazo[4,5-c]- quinolin-2-one methanesulfonic acid salt46

1-cyclobutyl-8-[6-[3-(dimethyl- amino)propoxy]-3-pyridyl]-3-methyl-imidazo[4,5-c]quinolin- 2-one methanesulfonic acid salt

Example 45

NMR Spectrum (methanesulfonic acid salt): ¹H NMR (500 MHz, DMSO-d6) δ2.11-2.21 (2H, m), 2.29-2.33 (3H, m), 2.32-2.46 (1H, m), 2.52-2.6 (1H,m), 2.83 (6H, s), 3.21-3.28 (2H, m), 3.55 (3H, s), 3.91 (1H, td),4.12-4.23 (2H, m), 4.27 (1H, td), 4.42 (2H, t), 5.79-5.9 (1H, m), 7.00(1H, dd), 7.98 (1H, dd), 8.16 (1H, d), 8.27 (1H, dd), 8.61 (1H, d), 8.71(1H, d), 8.94 (1H, s), 9.33 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=448.

Example 46

NMR Spectrum (free base): ¹H NMR (500 MHz, DMSO-d6) δ 1.39 (3H, d),1.92-2.01 (1H, m), 2.01-2.11 (1H, m), 2.34 (6H, s), 2.43 (1H, dd),2.51-2.61 (2H, m), 2.73 (1H, dd), 3.24 (2H, pd), 3.58 (3H, s), 5.31-5.41(1H, m), 5.43-5.53 (1H, m), 6.89 (1H, dd), 7.78 (1H, dd), 7.89 (1H, dd),8.18-8.22 (1H, m), 8.32 (1H, d), 8.51 (1H, dd), 8.69 (1H, s). NMRSpectrum (methanesulfonic acid salt): ¹H NMR (500 MHz, DMSO-d6) δ1.76-2.01 (2H, m), 2.08-2.22 (2H, m), 2.31 (3H, s), 2.41-2.49 (2H, m),2.83 (6H, s), 3.09 (2H, pd), 3.18-3.28 (2H, m), 3.51 (3H, s), 4.42 (2H,t), 5.51 (1H, p), 7.01 (1H, dd), 7.93 (1H, dd), 8.13 (1H, d), 8.24 (1H,dd), 8.42 (1H, d), 8.69 (1H, dd), 8.89 (1H, s), 9.34 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=432.

The bromo intermediates required for the preparation of examples 44-46were prepared as described below:

Intermediate V1:8-Bromo-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one

Tetrabutylammonium bromide (0.222 g, 0.69 mmol) was added to8-bromo-1-[(3R)-tetrahydrofuran-3-yl]-3H-imidazo[4,5-c]quinolin-2-one(2.3 g, 6.88 mmol), methyl iodide (1.291 mL, 20.65 mmol) and NaOH (0.551g, 13.77 mmol) in DCM (65 mL) and water (39 mL) and the resultingmixture stirred at ambient temperature overnight. The solvent wasremoved under reduced pressure and the crude product purified by FCC,elution gradient 2 to 5% MeOH in DCM, to afford the desired material asa yellow solid (1.80 g, 75%). NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ2.41-2.49 (1H, m), 2.59-2.65 (1H, m), 3.62 (3H, s), 4.00-4.06 (1H, m),4.21-4.48 (2H, m), 4.49-4.52 (1H, m), 5.69-5.77 (1H, m), 7.69 (1H, d),8.02 (1H, d), 8.64 (1H, s), 8.74 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=350.

The following compounds were prepared in an analogous fashion from theappropriate intermediate:

Intermediate Structure Name Intermediate W1

8-bromo-3-methyl-1-[(3S)- tetrahydrofuran-3-yl]imidazo-[4,5-c]quinolin-2-one Intermediate X1

8-bromo-1-cyclobutyl-3-methyl- imidazo[4,5-c]quinolin-2-one

Intermediate W1

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 2.40-2.48 (1H, m), 2.58-2.67(1H, m), 3.63 (3H, s), 3.98-4.05 (1H, m), 4.19-4.28 (2H, m), 4.46-4.51(1H, td), 5.68-5.76 (1H, m), 7.72 (1H, d), 8.07 (1H, d), 8.67 (1H, d),8.76 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=348.

Intermediate X1

NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.95-2.12 (2H, m), 2.52-2.59(2H, m), 3.17-3.28 (2H, m), 3.59 (3H, s), 5.18-5.27 (1H, m), 7.8 (1H,d), 8.02 (1H, d), 8.37 (1H, d), 8.70 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=332.

Intermediate V2:8-Bromo-1-[(3R)-tetrahydrofuran-3-yl]-3H-imidazo[4,5-c]quinolin-2-one

Triethylamine (2.60 mL, 18.69 mmol) was added to6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylic acid(2.1 g, 6.23 mmol) in DMF (30 mL) and the resulting mixture stirred atambient temperature for 1 h. Diphenyl phosphorazidate (3.43 g, 12.46mmol) was added and the resulting mixture stirred at 60° C. overnight.The reaction mixture was diluted with water (300 mL) and the solidscollected by filtration to afford the desired material as a yellow solid(2.0 g, 96%). NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 2.42-2.45 (2H,m), 3.85-3.90 (1H, m), 4.05-4.16 (2H, m), 4.16-4.25 (1H, m), 5.62-5.72(1H, m), 7.16-7.18 (1H, m), 7.74 (1H, d), 7.97 (1H, d), 8.68 (1H, s),8.73 (1H, s), 11.84 (1H, s).

Mass Spectrum: m/z (ES+)[M+H]+=334.

The following compounds were prepared in an analogous fashion from theappropriate intermediate

Intermediate Structure Name Intermediate W2

8-bromo-1-[(3S)-tetrahydrofuran- 3-yl]-3H-imidazo[4,5-c]quinolin- 2-oneIntermediate X2

8-bromo-1-cyclobutyl-3H- imidazo-[4,5-c]quinolin-2-one

Intermediate W2

Mass Spectrum: m/z (ES+)[M+H]+=334.

Intermediate X2

Mass Spectrum: m/z (ES+)[M+H]+=318.

Intermediate V3:6-Bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylic acid

Sodium hydroxide (0.657 g, 16.43 mmol) was added to ethyl6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylate (3g, 8.21 mmol) in THF (60 mL) and water (30 mL) and the resulting mixturestirred at 60° C. overnight. The aqueous component was removed underreduced pressure and the remaining solution was adjusted to pH 6 with 2M HCl. The solids were collected by filtration and dried in an oven toafford the desired material as a white solid (2.1 g, 76%). NMR Spectrum:¹H NMR (300 MHz, MeOH-d4) δ 2.05-2.08 (1H, m), 2.38-2.48 (1H, m),3.72-3.93 (4H, m), 4.83-5.01 (1H, m) 7.09 (1H, d), 8.04 (1H, d), 8.55(1H, s), 8.95 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=339.

The following compounds were prepared in an analogous fashion from theappropriate intermediate

Intermediate Structure Name Intermediate W3

6-bromo-4-[[(3S′)-tetra- hydro-furan-3-yl]amino]- quinoline-3-carboxylicacid Intermediate X3

6-bromo-4-(cyclobutyl- amino)quinoline-3- carboxylic acid

Intermediate W3

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.95-2.05 (1H, m), 2.31-2.41(1H, m), 3.79-3.87 (2H, m), 3.89-3.95 (2H, m), 4.82-4.92 (1H, m), 7.78(1H, d), 7.92-7.94 (1H, m), 8.44 (1H, d), 8.90 (1H, s), 13.3 (1H, s).Mass Spectrum: m/z (ES+)[M+H]+=337.

Intermediate X3

NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.81-1.95 (3H, m), 2.01-2.15(3H, m), 4.53-4.55 (1H, m), 7.74 (1H, d), 7.88 (1H, d), 8.25 (1H, s),8.89 (1H, s), 13.27 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=321.

Intermediate V4: Ethyl6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylate

DIPEA (7.77 mL, 44.51 mmol) was added to ethyl6-bromo-4-chloroquinoline-3-carboxylate (3.5 g, 11.13 mmol) and(R)-tetrahydrofuran-3-amine (1.939 g, 22.25 mmol) in DMF (40 mL) and theresulting mixture stirred at 100° C. overnight. The reaction mixture wascooled, filtered and the solid dried in an oven to afford the desiredmaterial as a white solid (3.00 g, 73.8%). NMR Spectrum: ¹H NMR (300MHz, MeOH-d4) δ 1.35 (3H, t), 1.96-2.01 (1H, m), 2.33-2.38 (1H, m), 3.73(2H, m), 3.94 (2H, m), 4.67 (1H, m), 7.77-7.89 (2H, m), 8.50 (1H, s),8.75 (1H, d), 8.87 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=365.

The following compounds were prepared in an analogous fashion from theappropriate intermediate.

Intermediate Structure Name Intermediate W4

ethyl 6-bromo-4-[[(3S)-tetra- hydrofuran-3-yl]amino]-quinoline-3-carboxylate Intermediate X4 *

ethyl 6-bromo-4-(cyclobutyl- amino)quinoline-3-carboxylate *The reactionwas stirred at 60° C. for 16 h.

Intermediate W4

NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.45 (3H, t), 2.12-2.19 (1H, m),2.48-2.55 (1H, m), 3.87-4.04 (2H, m), 4.12 (2H, td), 4.43 (2H, q),4.76-4.86 (1H, m), 7.80 (1H, dd), 7.95 (1H, d), 8.34 (1H, d), 9.14 (1H,s), 9.64 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=365.

Intermediate X4

NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.45 (3H, t), 1.77-2.01 (2H, m),2.16-2.31 (2H, m), 2.58-2.71 (2H, m), 4.45 (3H, m), 7.74 (1H, dd), 7.82(1H, d), 8.23 (1H, d), 9.09 (1H, s), 9.57 (1H, d) Mass Spectrum: m/z(ES+)[M+H]+=349.

The preparation of ethyl 6-bromo-4-chloroquinoline-3-carboxylate hasbeen described earlier.

Example 477-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-onemethanesulfonic acid salt

3-(Piperidin-1-yl)propan-1-ol (43.4 mg, 0.30 mmol) in THF (0.5 mL) wasadded dropwise to a stirred suspension of sodium hydride (24.22 mg, 0.61mmol) in THF (0.5 mL) at room temperature. The resulting suspension wasstirred for 10 minutes under nitrogen then7-fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one (100 mg, 0.25 mmol)in DMF (1.5 mL) added and the reaction mixture stirred at roomtemperature overnight. The reaction mixture was diluted with EtOAc (40mL), washed twice with water (20 mL), the organic layer dried overMgSO₄, filtered and evaporated to afford crude product. The crudeproduct was purified by FCC, elution gradient 0 to 4% 2N methanolicammonia in DCM, to afford the desired material as a white solid (80 mg,61.0%). The isolated material (79 mg) was dissolved in DCM (2 mL) andmethanesulfonic acid (16.07 mg, 0.17 mmol) in DCM added. The solutionwas evaporated to dryness to afford the methanesulfonic acid salt of thedesired material as a pale yellow solid (97 mg). NMR Spectrum(methanesulfonic acid salt): ¹H NMR (500 MHz, DMSO-d6) δ 1.40 (1H, dd),1.55-1.92 (6H, m), 2.06-2.26 (3H, m), 2.31 (3H, s), 2.59-2.77 (1H, m),2.82-3.03 (2H, m), 3.19-3.29 (2H, m), 3.38 (2H, td), 3.49 (5H, s),3.84-3.95 (1H, m), 4.12 (1H, dd), 4.19 (1H, t), 4.44 (2H, t), 4.76-5.07(1H, m), 7.04 (1H, dd), 7.96 (1H, d), 8.11 (1H, dt), 8.26 (1H, d), 8.54(1H, s), 8.95 (1H, s), 9.01 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=520.2

7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-onewas prepared as described below:

Intermediate K4:7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one

8-Bromo-7-fluoro-3-methyl-1-[(35)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one(250 mg, 0.66 mmol), (6-fluoropyridin-3-yl)boronic acid (120 mg, 0.85mmol) and 2M K₂CO₃ (1 mL, 2.00 mmol) were suspended in 1,4-dioxane (3mL), degassed, then [Pd-118] (22 mg, 0.03 mmol) added. The reaction washeated to 80° C. for 1 h under nitrogen then allowed to cool. Thereaction mixture was diluted with EtOAc (50 mL) then washed with water(2×25 mL), brine, the organic phase dried over MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by FCC, elutiongradient 0 to 4% 2N methanolic ammonia in DCM, to afford the desiredmaterial as an off-white solid (205 mg, 79%). NMR Spectrum: ¹H NMR (500MHz, DMSO-d6) δ 1.71-1.87 (2H, m), 2.14 (1H, d), 2.57-2.76 (1H, m),3.32-3.42 (1H, m), 3.49 (3H, s), 3.90 (1H, d), 4.06-4.16 (1H, m), 4.21(1H, t), 4.79-5.1 (1H, m), 7.36-7.54 (1H, m), 7.97 (1H, d), 8.32 (1H,d), 8.37 (1H, tt), 8.62 (1H, s), 8.95 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=397.

The preparation of8-bromo-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-onehas been described earlier.

Example 488-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-onemethanesulfonic acid salt

Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(103 mg, 0.13 mmol) was added to a3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy-N,N-dimethylpropan-1-amine(468 mg, 1.44 mmol),8-bromo-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one(500 mg, 1.32 mmol) and cesium carbonate (1285 mg, 3.95 mmol) in1,4-dioxane (5 mL) and water (2.5 mL). The resulting mixture was stirredat 80° C. for three h then allowed to cool. The reaction mixture wasdiluted with EtOAc (100 mL), washed twice with water (50 mL), theorganic layer dried over MgSO₄, filtered and evaporated to afford crudeproduct. The crude product was purified by FCC, elution gradient 0 to 4%2N methanolic ammonia in DCM, to afford the desired material as a whitesolid (130 mg, 19.87%). The material can also be isolated as themethanesulfonic acid salt by dissolving in DCM and treating with 1-1.1equivalents of methanesulfonic acid then concentrating the mixture invacuo and triturating the residue with Et₂O. NMR Spectrum (free base):¹H NMR (500 MHz, DMSO-d6) δ 1.77 (2H, t), 1.89 (2H, p), 2.11 (1H, d),2.16 (6H, s), 2.37 (2H, t), 2.54-2.72 (1H, m), 3.33-3.42 (1H, m), 3.49(3H, s), 3.89 (1H, d), 4.08 (1H, dd), 4.23 (1H, t), 4.33 (2H, t), 4.85(1H, s), 6.98 (1H, dd), 7.93 (1H, d), 8.11-8.24 (1H, m), 8.30 (1H, d),8.93 (1H, s). NMR Spectrum (methanesulfonic acid salt): ¹H NMR (500 MHz,DMSO-d6) δ 1.66-1.89 (2H, m), 2.04-2.26 (3H, m), 2.31 (3H, s), 2.59-2.7(1H, m), 2.84 (6H, d), 3.22-3.43 (3H, m), 3.50 (3H, s), 3.88 (1H, d),4.03-4.15 (1H, m), 4.22 (1H, t), 4.39 (2H, t), 4.85 (1H, t), 7.01 (1H,d), 7.96 (1H, d), 8.17-8.26 (1H, m), 8.30 (1H, d), 8.96 (1H, s), 9.35(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=498.

The following compounds were prepared in an analogous fashion from theappropriate intermediates.

Example Structure Name 49

8-[6-[3-(dimethylamino)- propoxy]-2-fluoro-3- pyridyl]-3-methyl-1-[(3S)-tetrahydrofuran-3-yl]- imidazo[4,5-c]quinolin- 2-one methanesulfonicacid salt 50

8-[6-[3-(dimethylamino)- propoxy]-2-fluoro-3- pyridyl]-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]- imidazo[4,5-c]quinolin- 2-one methanesulfonicacid salt 51

1-cyclobutyl-8-[6-[3- (dimethylamino)propoxy]- 2-fluoro-3-pyridyl]-3-methyl-imidazo[4,5-c]- quinolin-2-one methane- sulfonic acid salt 52

8-[6-[3-(dimethylamino)- propoxy]-2-fluoro-3- pyridyl]-3-methyl-1-(oxetan-3-yl)imidazo- [4,5-c]quinolin-2-one methanesulfonic acid salt

Example 49

NMR Spectrum (free base): ¹H NMR (500 MHz, DMSO-d6) δ 1.82-1.95 (2H, m),2.16 (6H, s), 2.36 (3H, t), 2.52-2.59 (1H, m), 3.54 (3H, s), 3.87 (1H,d), 4.11 (2H, dd), 4.21 (1H, d), 4.31 (2H, t), 5.76 (1H, s), 6.94 (1H,dd), 7.81 (1H, dt), 8.13 (1H, d), 8.20 (1H, dd), 8.57 (1H, d), 8.94 (1H,s). NMR Spectrum (methanesulfonic acid salt): ¹H NMR (500 MHz, DMSO-d6)δ 2.08-2.25 (2H, m), 2.31 (3H, s), 2.32-2.42 (1H, m), 2.52-2.59 (1H, m),2.84 (6H, s), 3.2-3.28 (2H, m), 3.54 (3H, s), 3.8-3.97 (1H, m),4.03-4.17 (2H, m), 4.22 (1H, td), 4.38 (2H, t), 5.64-5.97 (1H, m), 6.97(1H, d), 7.82 (1H, d), 8.15 (1H, d), 8.25 (1H, dd), 8.59 (1H, s), 8.96(1H, s), 9.35 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=466.

Example 50

NMR Spectrum (free base): ¹H NMR (500 MHz, DMSO-d6) δ 1.89 (2H, p), 2.16(6H, s), 2.36 (3H, t), 2.52-2.6 (1H, m), 3.54 (3H, s), 3.79-3.98 (1H,m), 4.04-4.18 (2H, m), 4.21 (1H, td), 4.31 (2H, t), 5.76 (1H, d), 6.94(1H, dd), 7.81 (1H, dt), 8.13 (1H, d), 8.20 (1H, dd), 8.57 (1H, d), 8.94(1H, s). NMR Spectrum (methanesulfonic acid salt): ¹H NMR (500 MHz,DMSO-d6) δ 2.1-2.25 (2H, m), 2.33 (3H, s), 2.35-2.44 (1H, m), 2.53-2.61(1H, m), 2.85 (6H, d), 3.26 (2H, s), 3.57 (3H, s), 3.81-3.98 (1H, m),4.07-4.17 (2H, m), 4.19-4.29 (1H, m), 4.39 (2H, t), 5.71-5.9 (1H, m),6.99 (1H, d), 7.91 (1H, d), 8.20 (1H, d), 8.27 (1H, dd), 8.65 (1H, s),9.06 (1H, s), 9.40 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=466.

Example 51

NMR Spectrum (free base): ¹H NMR (500 MHz, DMSO-d6) δ 1.79-1.95 (4H, m),2.16 (6H, s), 2.37 (2H, t), 2.4-2.49 (2H, m), 3.07 (2H, td), 3.50 (3H,s), 4.32 (2H, t), 5.40 (1H, p), 6.95 (1H, d), 7.80 (1H, d), 8.11 (1H,d), 8.22 (1H, dd), 8.44 (1H, s), 8.90 (1H, s). NMR Spectrum(methanesulfonic acid salt): ¹H NMR (500 MHz, DMSO-d6) δ 1.78-1.99 (2H,m), 2.08-2.23 (2H, m), 2.31 (3H, s), 2.38-2.48 (2H, m), 2.84 (6H, s),3.01-3.14 (2H, m), 3.2-3.29 (2H, m), 3.51 (3H, s), 4.38 (2H, t),5.28-5.58 (1H, m), 6.98 (1H, d), 7.83 (1H, d), 8.15 (1H, d), 8.23-8.39(1H, m), 8.46 (1H, s), 8.94 (1H, s), 9.38 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=450.

Example 52

NMR Spectrum (free base): ¹H NMR (500 MHz, DMSO-d6) δ 1.83-1.96 (2H, m),2.16 (6H, s), 2.36 (2H, t), 3.53 (3H, s), 4.32 (2H, t), 5.01 (2H, dd),5.25 (2H, t), 5.95-6.24 (1H, m), 6.94 (1H, dd), 7.82 (1H, dt), 8.13 (1H,d), 8.19 (1H, dd), 8.39 (1H, s), 8.95 (1H, s). NMR Spectrum(methanesulfonic acid salt): ¹H NMR (500 MHz, DMSO-d6) δ 2.09-2.25 (2H,m), 2.32 (3H, s), 2.85 (6H, s), 3.22-3.29 (2H, m), 3.55 (3H, s), 4.39(2H, t), 4.95-5.14 (2H, m), 5.26 (2H, t), 6.10 (1H, p), 6.98 (1H, d),7.85 (1H, d), 8.17 (1H, d), 8.25 (1H, dd), 8.45 (1H, s), 9.01 (1H, s),9.36 (1H, s) Mass Spectrum: m/z (ES+)[M+H]+=452.

The3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy-N,N-dimethylpropan-1-amineused for these examples was prepared directly before use by treating3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (1 equiv)with 4,4,4′,4′-5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2equiv), potassium acetate (3 equiv) and[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex withDCM (1:1) (0.1 equiv) in 1,4-dioxane at 100° C. for 6 h. This mixturewas allowed to cool then used directly in the subsequent reaction.

The preparation of3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine and therequired bromo intermediates have been described previously.

Example 537-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-2-one

3-(Piperidin-1-yl)propan-1-ol (0.053 mL, 0.35 mmol) was added slowly toa slurry of sodium hydride (31.5 mg, 0.79 mmol) in THF (7 mL) and thesolution stirred at ambient temperature for 30 minutes.7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-2-one(125 mg, 0.32 mmol) in THF (3 mL) was added to the reaction mixture viasyringe over a period of 1 minute and the reaction stirred for 24 h. Thereaction was quenched with water then extracted into DCM, the organicphase separated and concentrated in vacuo. The crude product waspurified by FCC, elution gradient 0 to 10% 1M methanolic ammonia in DCM,and the resultant oil triturated with Et₂O to afford the desiredmaterial as a white solid (92 mg, 56%). NMR Spectrum: ¹H NMR (500 MHz,CDCl₃) δ 1.38-1.52 (2H, m), 1.61 (4H, p), 1.92 (2H, dd), 2.03 (2H, dt),2.43 (4H, s), 2.47-2.58 (2H, m), 2.94 (2H, d), 3.53-3.63 (5H, m), 4.22(2H, dd), 4.42 (2H, t), 5.01 (1H, s), 6.89 (1H, dd), 7.85-7.96 (2H, m),8.26 (1H, s), 8.44 (1H, s), 8.71 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=520.

The following compounds were prepared in an analogous fashion from theappropriate intermediates.

Example Structure Name 54 *

3-methyl-8-[6-[3-(1-piperidyl)- propoxy]-3-pyridyl]-1-[(3R)-tetrahydrofuran-3-yl]imidazo- [4,5-c]quinolin-2-one methane sulfonicacid salt 55 **

3-methyl-8-[6-[3-(1-piperidyl)- propoxy]-3-pyridyl]-1-[(3S)-tetrahydrofuran-3-yl]imidazo- [4,5-c]quinolin-2-one 56 ***

3-methyl-1-(oxetan-3-yl)-8-[6- [3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin- 2-one trifluoroacetic acid salt 57 ***

1-cyclobutyl-3-methyl-8-[6-[3- (1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin- 2-one trifluoroacetic acid salt 58 ****

1-cyclobutyl-3-methyl-8-[6-(3- pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin- 2-one 59 *****

3-methyl-8-[6-(3-pyrrolidin-1- ylpropoxy)-3-pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo- [4,5-c]quinolin-2-one 60 ******

8-[6-[3-(azetidin-1-yl)propoxy]- 3-pyridyl]-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo- [4,5-c]quinolin-2-one *The reaction wasstirred at ambient temperature for 4 h then at 45° C. for 2 h. Thematerial could also be isolated as a methanesulfonic acid salt bydissolving in DCM, treating with methanesulfonic acid (~1 equiv) andconcentrating in vacuo then triturating the residue with Et₂O. **Thereaction was stirred at ambient temperature for 4 h then at 45° C. for 2h. ***The reaction was stirred at r.t. for 4 h then at 45° C. for 2 h.The material could also be isolated as a trifluoroacetic acid salt bydissolving in DCM, treating with trifluoroacetic acid (~1 equiv) andconcentrating in vacuo then triturating the residue with Et₂O. ****Thereaction was stirred at 50° C. for overnight. The material could also beisolated as a methanesulfonic acid salt by dissolving in DCM, treatingwith methanesulfonic acid (~1 equiv) and concentrating in vacuo.*****The reaction was stirred at r.t. for 3 days. ******The reaction wasstirred at r.t. for 2 h.

Example 54

NMR Spectrum (methanesulfonic acid salt): ¹H NMR (500 MHz, CDCl₃) δ1.5-1.63 (2H, m), 1.7-1.98 (7H, m), 2.2-2.3 (2H, m), 2.45 (2H, dtd),2.59-2.72 (2H, m), 2.82 (3H, s), 3.63 (3H, s), 3.79-3.87 (1H, m), 3.97(1H, td), 4.19-4.33 (2H, m), 4.37-4.45 (1H, m), 4.46 (2H, t), 5.81-5.93(1H, m), 6.87 (1H, dd), 7.84 (1H, dd), 8.05 (1H, dd), 8.23 (1H, d), 8.56(1H, dd), 8.58 (1H, d), 8.74 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=488.

Example 55

NMR Spectrum: ¹H NMR (500 MHz, CDCl₃) δ 1.36-1.51 (2H, m), 1.61 (4H, p),2.02 (2H, dt), 2.44 (5H, dtd), 2.48-2.55 (2H, m), 2.59-2.71 (1H, m),3.63 (3H, s), 3.98 (1H, td), 4.21-4.33 (2H, m), 4.41 (3H, t), 5.86 (1H,qd), 6.87 (1H, dd), 7.85 (1H, dd), 8.03 (1H, dd), 8.17-8.25 (1H, m),8.5-8.59 (2H, m), 8.73 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=488.

Example 56

NMR Spectrum (free base): ¹H NMR (500 MHz, CDCl₃) δ 0.07 (1H, s), 1.45(2H, s), 1.57-1.64 (3H, m), 1.99-2.06 (2H, m), 2.42 (4H, s), 2.47-2.54(2H, m), 3.62 (3H, s), 4.41 (2H, t), 5.18-5.25 (2H, m), 5.37 (2H, t),6.08-6.18 (1H, m), 6.87 (1H, dd), 7.87 (1H, dd), 7.97 (1H, dd), 8.24(1H, d), 8.52-8.58 (2H, m), 8.75 (1H, s). NMR Spectrum (trifluoroaceticacid salt): ¹H NMR (500 MHz, DMSO-d6) δ 1.6-1.78 (4H, m), 1.85 (2H, d),2.14-2.23 (2H, m), 2.94 (1H, s), 3.2-3.28 (2H, m), 3.51 (2H, d), 3.58(3H, s), 4.44 (2H, t), 5.05-5.12 (2H, m), 5.28 (2H, t), 6.23-6.31 (1H,m), 7.02 (1H, d), 8.05-8.37 (4H, m), 8.60 (1H, s), 8.74 (1H, d), 9.17(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=474.

Example 57

NMR Spectrum (free base): ¹H NMR (500 MHz, CDCl₃) δ 1.45 (2H, d), 1.60(4H, p), 1.86-2.12 (4H, m), 2.43 (4H, s), 2.47-2.63 (4H, m), 3.24 (2H,pd), 3.58 (3H, s), 4.42 (2H, t), 5.36 (1H, p), 6.89 (1H, dd), 7.77 (1H,dd), 7.90 (1H, dd), 8.21 (1H, d), 8.32 (1H, d), 8.51 (1H, dd), 8.69 (1H,s). NMR Spectrum (trifluoroacetic acid salt): ¹H NMR (500 MHz, DMSO-d6)δ 1.42 (2H, s), 1.58-1.76 (4H, m), 1.82-1.97 (4H, m), 2.14-2.28 (2H, m),2.93 (2H, d), 3.06-3.14 (2H, m), 3.21-3.29 (2H, m), 3.53 (3H, s), 4.44(2H, t), 5.51-5.58 (1H, m), 6.99-7.05 (1H, m), 8.00 (1H, d), 8.17 (1H,d), 8.26 (1H, d), 8.27 (1H, d), 8.46 (1H, s), 8.71 (1H, d), 8.97 (2H,s). Mass Spectrum: m/z (ES+)[M+H]+=472.

Example 58

NMR Spectrum (free base): ¹H NMR (500 MHz, DMSO-d6) δ 1.67-1.73 (4H, m),1.86-1.99 (4H, m), 2.45-2.5 (6H, m), 2.57 (2H, t), 3.09 (2H, pd), 3.51(3H, s), 4.39 (2H, t), 5.52 (1H, p), 6.99 (1H, dd), 7.92 (1H, dd), 8.12(1H, d), 8.20 (1H, dd), 8.41 (1H, d), 8.67 (1H, dd), 8.88 (1H, s). NMRSpectrum (methanesulfonic acid salt): ¹H NMR (500 MHz, DMSO-d6) δ1.84-1.98 (4H, m), 2.01-2.1 (2H, m), 2.13-2.23 (2H, m), 2.32 (3H, s),3.03-3.14 (4H, m), 3.28-3.36 (4H, m), 3.54 (3H, s), 3.58-3.67 (2H, m),4.45 (2H, t), 5.52-5.63 (1H, m), 7.04 (1H, dd), 8.06 (1H, d), 8.19 (1H,d), 8.27 (1H, dd), 8.49 (1H, s), 8.71-8.74 (1H, m), 9.03 (1H, s), 9.50(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=458.

Example 59

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.68-1.86 (6H, m), 1.95 (2H,m), 2.15 (1H, m), 2.51-2.75 (7H, m), 3.40 (1H, m), 3.49 (3H, s), 3.92(1H, m), 4.15 (2H, m), 4.38 (2H, m), 4.97 (1H, m), 6.98 (1H, m),7.91-8.89 (6.82H, m). Mass Spectrum: m/z (ES+)[M+H]+=488.3.

Example 60

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.80 (4H, m), 2.10 (3H, m),2.68 (3H, m), 3.35 (5H, m), 3.49 (3H, m), 3.92 (1H, m), 4.15 (2H, m),4.33 (2H, m), 4.93 (1H, m), 6.98 (1H, m), 7.91-8.89 (6.92H, m). MassSpectrum: m/z (ES+)[M+H]+=474.2.

The required fluoro intermediates for Examples 53-60 have either beendescribed previously or were prepared from the appropriate bromointermediates as described below:

Intermediate F5:7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-2-one

(6-Fluoropyridin-3-yl)boronic acid (0.445 g, 3.16 mmol),8-bromo-7-fluoro-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (1g, 2.63 mmol) and 2M K₂CO₃ (3.95 mL, 7.89 mmol) were suspended indioxane (3 mL) and water (0.75 mL). The reaction was degassed withnitrogen and thendichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (0.086g, 0.13 mmol) was added and the reaction heated to 80° C. for 1 h in themicrowave reactor. The mixture was allowed to cool, diluted with waterthen extracted with DCM (2×100 mL). The combined organic phases wereseparated and concentrated in vacuo. The crude product was purified byFCC, elution gradient 0 to 10% methanolic ammonia in DCM, to afford thedesired material as a beige solid (0.92 g, 88%). NMR Spectrum: ¹H NMR(500 MHz, DMSO-d6) δ 1.90 (2H, dd), 2.69 (2H, qt), 3.49-3.59 (5H, m),3.97-4.06 (2H, m), 5.08 (1H, tt), 7.38-7.45 (1H, m), 7.96 (1H, d),8.34-8.42 (2H, m), 8.61-8.65 (1H, m), 8.95 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=397

The following fluoro intermediates were prepared in an analogousfashion:

Intermediate Structure Name Intermediate V5

8-(6-fluoro-3-pyridyl)-3-methyl- 1-[(3R)-tetrahydrofuran-3-yl]-imidazo[4,5-c]quinolin-2-one Intermediate W5

8-(6-fluoro-3-pyridyl)-3-methyl- 1-[(3S)-tetrahydrolfuran-3-yl]-imidazo[4,5-c]quinolin-2-one Intermediate G5

8-(6-fluoro-3-pyridyl)-3-methyl- 1-(oxetan-3-yl)imidazo[4,5-c]-quinolin-2-one Intermediate X5

1-cyclobutyl-8-(6-fluoro-3- pyridyl)-3-methyl-imidazo-[4,5-c]quinolin-2-one

Intermediate V5

NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 2.34-2.45 (1H, m), 2.52-2.67(1H, m), 3.55 (3H, s), 3.91 (1H, td), 4.13-4.23 (2H, m), 4.27 (1H, td),5.76-5.92 (1H, m), 7.38 (1H, dd), 8.02 (1H, dd), 8.18 (1H, d), 8.49 (1H,ddd), 8.68 (1H, d), 8.77 (1H, d), 8.96 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=365.

Intermediate W5

NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 2.33-2.44 (1H, m), 2.53-2.67(1H, m), 3.55 (3H, s), 3.91 (1H, td), 4.13-4.22 (2H, m), 4.27 (1H, td),5.79-5.9 (1H, m), 7.3-7.41 (1H, m), 8.02 (1H, dd), 8.18 (1H, d), 8.49(1H, ddd), 8.68 (1H, d), 8.77 (1H, d), 8.96 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=365.

Intermediate G5

NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 3.55 (3H, s), 5.07 (2H, dd),5.28 (2H, t), 6.09-6.31 (1H, m), 7.29-7.43 (1H, m), 8.02 (1H, dd), 8.18(1H, d), 8.49 (1H, ddd), 8.56 (1H, d), 8.77 (1H, d), 8.97 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=351

Intermediate X5

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.77-2.01 (2H, m), 2.46 (2H,ddt), 3.09 (2H, pd), 3.51 (3H, s), 5.53 (1H, p), 7.32-7.44 (1H, m), 7.96(1H, dd), 8.15 (1H, d), 8.43-8.54 (2H, m), 8.75 (1H, d), 8.91 (1H, s).Mass Spectrum: m/z (ES+)[M+H]+=349.

The preparation of the bromo intermediates required for the abovereactions have been described previously.

Example 618-[2-Fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one

A solution of 3-(pyrrolidin-1-yl)propan-1-ol (0.047 g, 0.36 mmol) in THF(2 mL) was added slowly to a stirred suspension of sodium hydride (0.038g, 0.96 mmol) in THF (2.0 mL) and the resulting suspension stirred atr.t. for 30 minutes. A solution of8-(2,6-difluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one(0.12 g, 0.34 mmol) in DMF (2 mL) was added slowly and the reactionstirred overnight. Water was added and the mixture stirred for 30minutes before being extracted with EtOAc (50 mL). The organics werewashed with sat. brine (25 mL), dried and evaporated to give crudeproduct. The crude product was purified by FCC, elution gradient 0 to10% (1% NH₃ in MeOH) in DCM, to afford the desired material as a whitesolid (0.005 g, 4%). NMR Spectrum: ¹H NMR (500 MHz, CDCl₃) δ 0.8-0.92(1H, m), 1.21-1.29 (1H, m), 1.88-1.97 (2H, m), 1.99-2.1 (4H, m), 2.23(1H, d), 2.26-2.36 (2H, m), 2.77 (1H, qd), 2.9-3.16 (4H, m), 3.53-3.56(1H, m), 3.57 (3H, s), 3.98-4.09 (1H, m), 4.12-4.21 (1H, m), 4.45 (2H,t), 4.53 (1H, t), 4.9-5.01 (1H, m), 6.80 (1H, dd), 7.75 (1H, d), 7.93(1H, dd), 8.22 (1H, d), 8.42 (1H, s), 8.71 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=506.

The preparation of8-(2,6-difluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-oneis described below:

Intermediate D5:8-(2,6-difluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one

(2,6-Difluoropyridin-3-yl)boronic acid (158 mg, 0.99 mmol) and8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one (300 mg,0.83 mmol) were suspended in dioxane (8 mL) and 2M K₂CO₃ (2.071 mL, 4.14mmol). The mixture was degassed with nitrogen anddichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (27.0mg, 0.04 mmol) added. The resulting suspension was heated at 80° C. for1 h in a microwave reactor. The reaction mixture was diluted with EtOActhen washed with water (20 mL), brine and the organic phase dried overMgSO₄, filtered and concentrated in vacuo. The crude product waspurified by FCC, elution gradient 0 to 10% MeOH in DCM, to afford thedesired material as a brown solid (196 mg, 60%). NMR Spectrum: ¹H NMR(500 MHz, DMSO-d6) δ 1.82 (2H, hept), 2.15 (1H, d), 2.55-2.67 (1H, m),3.36-3.44 (1H, m), 3.51 (3H, s), 3.92 (1H, d), 4.06-4.14 (1H, m), 4.29(1H, t), 4.91 (1H, ddd), 7.42 (1H, dd), 7.85-7.91 (1H, m), 8.19 (1H, d),8.47 (1H, s), 8.56 (1H, dt), 8.95 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=397.

The preparation of8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one has beendescribed previously.

Examples 62 & 638-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-oneand8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one

8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one:8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one(1:1 mixture) (400 mg, 1.01 mmol),N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine(227 mg, 1.01 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(160 mg, 0.20 mmol) were suspended in a mixture of dioxane (5 mL) andwater (0.5 mL) and Cs₂CO₃ (661 mg, 2.03 mmol) added. The reaction washeated to 120° C. for 1 h in the microwave reactor then allowed to cool.The reaction mixture was evaporated to dryness and redissolved in EtOAc(100 mL), washed sequentially with water (2×20 mL), the organic layerdried over Na₂SO₄, filtered and evaporated to afford crude product. Thecrude product was purified by preparative HPLC, using decreasingly polarmixtures of water (containing 0.03% NH₃) and MeCN as eluents, to affordthe desired material as a racemic mixture. The mixture was purified bypreparative chiral-HPLC on a Chiralpak IA column, eluting isocraticallywith 10% isopropyl alcohol in heptane (modified with 0.2% diethylamine)as eluent to deliver the two separated isomers.

Example 62

Isomer 1 (12 mg) NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.73-1.85(1H, m), 1.84-1.96 (2H, m), 2.09-2.26 (9H, s), 2.35-2.50 (4H, m),3.21-3.26 (3H, s), 3.45-3.58 (3H, s), 4.05-4.14 (1H, m), 4.33-4.42 (2H,m), 5.45-5.56 (1H, m), 6.97-7.04 (1H, m), 7.90-7.98 (1H, m), 8.01-8.09(1H, m), 8.26-8.33 (1H, m), 8.48-8.54 (1H, m), 8.91-8.96 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=494.

Example 63

Isomer 2 (12 mg) NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.75-1.82(1H, m), 1.85-1.97 (2H, m), 2.11-2.26 (9H, s), 2.37-2.50 (4H, m),3.21-3.26 (3H, s), 3.46-3.56 (3H, s), 4.07-4.13 (1H, m), 4.33-4.42 (2H,m), 5.47-5.58 (1H, m), 6.97-7.04 (1H, m), 7.90-7.98 (1H, m), 8.01-8.09(1H, m), 8.27-8.34 (1H, m), 8.49-8.54 (1H, s), 8.91-8.96 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=494.

The preparation of8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one:8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one(1:1 mixture) is described below:

Intermediate Y1:8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-oneand8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one(1:1 Mixture)

A mixture of8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one:8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one(1:1 mixture) (2.8 g, 7.33 mmol), sodium hydroxide (440 mg, 11.00mmol,), tetrabutylammonium bromide (240 mg, 0.75 mmol) and methyl iodide(1.6 g, 11.27 mmol) in DCM (150 mL) and water (100 mL) was stirred for12 h at r.t. The resulting mixture was concentrated in vacuo and theresidue triturated with water. The solids were collected by filtrationand dried to afford the desired material as a white solid (2.5 g, 86%).NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.76-1.86 (1H, m), 2.11-2.32(4H, m), 2.41-2.44 (1H, m), 3.27 (3H, s), 3.30 (3H, s), 4.12-4.15 (1H,m), 5.38-5.45 (1H, m), 7.96 (1H, d), 8.53 (1H, d), 8.94 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=394.

Intermediate Y2:8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-oneand8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one(1:1 Mixture)

A mixture of6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylicacid:6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylicacid (1:1 mixture) (2.9 g, 7.53 mmol) and triethylamine (2.3 g, 22.73mmol) in DMA (20 mL) was stirred at r.t. for 30 mins. Diphenylphosphorazidate (2.5 g, 9.09 mmol) was added and the resulting solutionstirred for 2 h at 60° C. The reaction mixture was allowed to cool andthe solids collected by filtration. The solid was dried in an oven underreduced pressure to afford the desired material as a white solid (2.8 g,97%). NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.78-1.88 (1H, m),2.11-2.31 (4H, m), 2.41-2.45 (1H, m), 3.27 (3H, s), 4.08-4.15 (1H, m),5.34-5.39 (1H, m), 7.92 (1H, d), 8.51 (1H, d), 8.68 (1H, s).

Mass Spectrum: m/z (ES+)[M+H]+=380.

Intermediate Y3:6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylicacid and6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylicacid (1:1 Mixture)

A mixture of ethyl6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate:ethyl6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate(1:1 mixture) (3.4 g, 8.23 mmol) and 2N sodium hydroxide (12 mL) in MeOH(15 mL) and THF (15 mL) was stirred for 12 h at r.t. The pH of thesolution was adjusted to 3 with 1M HCl and the resultant solid collectedby filtration and dried to afford the desired material as a white solid(2.9 g, 91%). NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.61-1.71 (2H,m), 1.76-1.86 (1H, m), 1.92-2.03 (1H, m), 2.11-2.26 (2H, m), 3.21 (3H,s), 3.86-3.96 (1H, m), 4.56-4.64 (1H, m), 7.70 (1H, d), 8.56 (1H, d),8.88 (1H, s), 13.31 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=383.

Intermediate Y4: Ethyl6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylateand Ethyl6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate(1:1 Mixture)

A mixture of ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (2g, 6.01 mmol), (1R,3R)-3-methoxycyclopentanamine hydrochloride and(1S,3S)-3-methoxycyclopentanamine hydrochloride (1:1 mixture) (1.4 g,9.21 mmol) and DIPEA (1.6 g, 12.38 mmol) in DMA (10 mL) was stirred for2 h at 80° C. The reaction mixture was allowed to cool and the residuetriturated with water. The solids were collected by filtration and driedto afford the desired material as a white solid (2.4 g, 97%). MassSpectrum: m/z (ES+)[M+H]+=411.

The preparation of ethyl6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate has been describedpreviously.

Examples 64 & 651-[(1R,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-oneand1-[(1S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one

A mixture of 3-(piperidin-1-yl)propan-1-ol (175 mg, 1.22 mmol) and NaH(122 mg, 3.06 mmol) in THF (10 mL) was stirred under nitrogen at 0° C.for 30 min then8-(6-fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one:8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one(1:1 mixture) (400 mg, 1.02 mmol) added. The resulting mixture wasstirred at r.t. for 1 h then was quenched with water (50 mL), extractedwith EtOAc (3×50 mL), the organic layer was dried over Na₂SO₄, filteredand evaporated to afford yellow oil. The crude liquid was trituratedwith heptane to give the desired material as a mixture of isomers (350mg, 66.6%) as a yellow solid. The racemic mixture was purified bypreparative chiral-HPLC on an AD column, eluting with 10% isopropylalcohol in hexane (modified with 0.1% diethylamine) as eluent, andfractions containing the separated isomers evaporated to dryness.

Example 64

Isomer 1 (120 mg) NMR Spectrum: ¹H NMR (300 MHz, MeOH-d4) δ 1.61-1.71(2H, m), 1.76-1.86 (1H, m), 1.92-2.03 (1H, m), 2.11-2.26 (2H, m), 3.21(3H, s), 3.86-3.96 (1H, m), 4.56-4.64 (1H, m), 7.70 (1H, d), 8.56 (1H,d), 8.88 (1H, s), 13.31 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=516.

Example 65

Isomer 2 (120 mg) NMR Spectrum: ¹H NMR (300 MHz, MeOH-d4) δ 1.53 (2H,q), 1.67 (4H, p), 1.89-2.14 (3H, m), 2.23-2.41 (3H, m), 2.47-2.71 (8H,m), 3.40 (3H, s), 3.58 (3H, s), 4.17-4.18 (1H, m), 4.41 (2H, t), 5.62(1H, p), 6.94 (1H, d), 7.88 (1H, d), 8.02-8.17 (2H, m), 8.38 (1H, d),8.51 (1H, d), 8.76 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=516.

The following compounds were prepared in an analogous fashion from8-(6-fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one:8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one(1:1 mixture) and the appropriate alcohol.

Example Structure Name 66 & 67 *

1-[(1S,3S)-3-methoxycyclo- pentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3- pyridyl]imidazo[4,5-c]- quinolin-2-one and

1-[(1R,3R)-3-methoxycyclo- pentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3- pyridyl]imidazo[4,5-c]- quinolin-2-one *Thereaction was stirred at r.t. for 5 h. The isomers were separated bypreparative chiral-HPLC on an AD column, eluting with 10% isopropylalcohol in hexane (modified with 0.1% diethylamine) as eluent.

Example 66

Isomer 1 (105 mg) NMR Spectrum: ¹H NMR (300 MHz, CDCl₃) δ 1.91-2.05 (5H,m), 2.14-2.18 (2H, m), 2.22-2.46 (3H, m), 2.52-2.83 (8H, m), 3.39 (3H,s), 3.62 (3H, s), 4.20 (1H, p), 4.47 (2H, t), 5.62 (1H, q), 6.91 (1H,d), 7.83 (1H, d), 7.94 (1H, d), 8.24 (1H, d), 8.36 (1H, d), 8.53 (1H,d), 8.73 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=502.

Example 67

Isomer 2 (105 mg) NMR Spectrum: ¹H NMR (300 MHz, CDCl₃) δ 1.80-2.00 (5H,m), 2.12-2.18 (2H, m), 2.35-2.55 (3H, m), 2.63-2.83 (8H, m), 3.40 (3H,s), 3.62 (3H, s), 4.20 (1H, t), 4.47 (2H, t), 5.61 (1H, p), 6.91 (1H,d), 7.83 (1H, d), 7.94 (1H, d), 8.25 (1H, d), 8.36 (1H, d), 8.53 (1H,d), 8.73 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=502

The preparation of8-(6-fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one:8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one(1:1 mixture) is described below.

Intermediate O5:8-(6-Fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-oneand8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one(1:1 Mixture)

A mixture of8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one(1:1 mixture) (1.5 g, 3.99 mmol), (6-fluoropyridin-3-yl)boronic acid(0.674 g, 4.78 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.314 g, 0.40 mmol) in dioxane:water (10:1 mixture) (16.5 mL) washeated to 120° C. for 45 mins in the microwave reactor then allowed tocool and concentrated in vacuo. The crude product was purified by FCC,elution gradient 0 to 10% MeOH in DCM, to afford the desired material asa yellow solid (1.20 g, 77%). NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ1.91-1.99 (1H, m), 2.21-2.36 (3H, m), 2.58-2.78 (2H, m), 3.38 (3H, s),3.62 (3H, s), 4.15-4.17 (1H, m), 5.52-5.65 (1H, m), 7.12 (1H, dd), 7.83(1H, dd), 8.13 (1H, td), 8.31 (1H, d), 8.40 (1H, d), 8.59 (1H, d), 8.76(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=393.

The preparation of8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one(1:1 mixture) has been described previously.

Examples 68 & 698-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-oneand8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one

Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (107 mg, 0.13 mmol) was addedto a3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy-N,N-dimethylpropan-1-amine(474 mg, 1.46 mmol),8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one(1:1 mixture) (500 mg, 1.33 mmol) and cesium carbonate (1299 mg, 3.99mmol) in 1,4-dioxane (10 mL) and water (2.5 mL). The resulting mixturewas stirred at 80° C. for 5 h then allowed to cool. The crude productwas purified by C18-FCC, elution gradient 5 to 50% MeOH in water, toafford the desired material as a mixture of isomers (350 mg, 53.4%). Theracemic mixture was purified by preparative chiral HPLC on a ChiralcelIC column, eluting with isopropyl alcohol, and fractions containing theseparated isomers evaporated to dryness.

Example 68

Isomer 1 (50 mg) NMR Spectrum: ¹H NMR (300 MHz, MeOH-d4) δ 1.90-1.96(1H, m), 2.12-2.13 (2H, m), 2.20-2.31 (3H, m), 2.47-2.50 (1H, m), 2.54(6H, s), 2.68-2.70 (1H, m), 2.78-2.90 (2H, m), 3.36 (3H, s), 3.60 (3H,s), 4.17-4.18 (1H, m), 4.43 (2H, t), 5.55-5.67 (1H, m), 6.89 (1H, d),7.80-7.91 (1H, m), 8.07-8.20 (2H, m), 8.48 (1H, s), 8.82 (1H, s).

Mass Spectrum: m/z (ES+)[M+H]+=494.

Example 69

Isomer 2 (45 mg) (containinated with 0.38 equivalents of diethylamine)NMR Spectrum: ¹H NMR (300 MHz, MeOH-d4) δ 1.93-1.95 (1H, m), 2.29-2.51(6H, m), 2.60-2.77 (2H, m), 2.95 (6H, s), 3.36-3.38 (4H, s), 3.60 (3H,s), 4.17-4.18 (1H, m), 4.48 (2H, t), 5.62-5.63 (1H, m), 6.92 (1H, d),7.85 (1H, d), 8.15-8.20 (2H, m), 8.48 (1H, s), 8.82 (1H, s).

Mass Spectrum: m/z (ES+)[M+H]+=494.

The preparation of8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one:8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-one(1:1 mixture) has been described previously.

Examples 70 & 718-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-oneand8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one

8-Bromo-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one:8-bromo-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one(1:1 mixture) (500 mg, 1.27 mmol),N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine(284 mg, 1.27 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(200 mg, 0.25 mmol) were suspended in a mixture of dioxane: water (10:1mixture, 20 mL) and Cs₂CO₃ (826 mg, 2.54 mmol) added. The reaction washeated to 120° C. for 1 h in the microwave reactor then allowed to cool.The reaction mixture was evaporated to dryness and redissolved in EtOAc(100 mL), washed sequentially with water (2×20 mL), the organic layerdried over Na₂SO₄, filtered and evaporated to afford crude product. Thecrude product was purified by preparative HPLC, using decreasingly polarmixtures of water (containing 0.03% NH₃) and MeCN as eluents, to affordthe desired material as a racemic mixture. The mixture was purified bypreparative chiral-HPLC on a Chiralpak IA column, eluting isocraticallywith 10% IPA in heptane (modified with 0.2% diethylamine) as eluent todeliver the two separated isomers.

Example 70

Isomer 1 (250 mg) NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.83-2.06(5H, m), 2.14-2.19 (6H, s), 2.26-2.51 (5H, m), 3.02-3.07 (3H, s),3.47-3.64 (3H, s), 3.86-3.96 (1H, m), 4.33-4.41 (2H, m), 5.26-5.40 (1H,m), 6.94-7.01 (1H, d), 7.89-7.97 (1H, d), 7.98-8.06 (1H, m), 8.39-8.49(2H, m), 8.92-8.97 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=494.

Example 71

Isomer 2 (250 mg) NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.83-2.08(5H, m), 2.13-2.18 (5H, s), 2.24-2.56 (4H, m), 3.02-3.07 (3H, s),3.50-3.55 (3H, s), 3.85-3.96 (1H, m), 4.33-4.41 (2H, m), 5.25-5.39 (1H,m), 6.94-7.01 (1H, m), 7.87-7.95 (1H, m), 7.97-8.05 (1H, m), 8.35-8.50(2H, m), 8.91-8.96 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=494.

The preparation of8-bromo-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-oneand8-bromo-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one(1:1 mixture) is described below:

Intermediate Z1:8-Bromo-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-oneand8-bromo-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one(1:1 Mixture)

NaH (0.213 g, 8.88 mmol) was added portionwise to8-bromo-7-fluoro-1-[(1R,3S)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one:8-bromo-7-fluoro-1-[(1S,3R)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one(1:1 mixture) (1.3 g, 3.55 mmol) in DMF (10 mL) at −20° C. undernitrogen and the resulting mixture stirred at 0° C. for 30 minutes.Methyl iodide (0.444 mL, 7.10 mmol) was added dropwise to the mixture at−20° C. under nitrogen and the resulting mixture was stirred at r.t. for16 h. The reaction mixture was poured into water (20 mL), the solidfiltered and dried to afford the desired material as a brown solid (1.30g, 93%). NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.96-2.02 (3H, t),2.22-2.51 (3H, m), 3.30-3.32 (3H, s), 3.97 (1H, m), 5.26-5.31 (1H, m),7.89-7.52 (1H, d), 8.74 (1H, d), 8.93 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=396.

Intermediate Z2:8-Bromo-7-fluoro-1-[(1R,3S)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-oneand8-bromo-7-fluoro-1-[(1S,3R)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one(1:1 Mixture)

A mixture of triethylamine (2.105 mL, 15.10 mmol) and6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylicacid:6-bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylicacid (1:1 mixture) (2 g, 5.03 mmol) in DMF (10 mL) was stirred for 1 h.Diphenyl phosphorazidate (1.663 g, 6.04 mmol) was added and theresulting solution stirred overnight at 60° C. The reaction mixture waspoured into water, the solids collected by filtration and dried toafford the desired material as a yellow solid (1.3 g, 71%). NMRSpectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.88 (2H, dt), 1.97-2.10 (1H, m),2.17 (1H, m), 2.38 (2H, m), 4.23-4.30 (1H, m), 5.27 (1H, m), 7.88 (1H,m), 8.69 (1H, s), 8.80 (1H, d), 11.77 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=366.

Intermediate Z3:6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylicacid and6-bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylicacid (1:1 Mixture)

A mixture of ethyl6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylate:ethyl6-bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylate(1:1 mixture) (3 g, 7.55 mmol) and sodium hydroxide (0.604 g, 15.10mmol) in THF (10 mL) and water (5 mL) was stirred for 16 h at 60° C. Theorganics were removed in vacuo and the pH of the resultant mixtureadjusted to 6-7 with 2M HCl. The resultant solid collected by filtrationand dried to afford the desired material as a grey solid (2.0 g, 72%).NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.68-1.82 (3H, m), 1.90-1.98(1H, m), 2.26 (2H, m), 2.51 (4H, s), 4.26 (1H, s), 4.68 (1H, s), 7.86(1H, d), 8.62 (1H, d), 8.93 (1H, s), 10.95 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=369.

Intermediate Z4: Ethyl6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylateand ethyl6-bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carboxylate(1:1 Mixture)

DIPEA (3.94 mL, 22.55 mmol) was added to a mixture ofcis-3-aminocyclopentanol hydrochloride (1.49 g, 10.83 mmol) and ethyl6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (3 g, 9.02 mmol) in DMA(20 mL) under nitrogen and the resulting mixture stirred at 100° C. for6 h. The reaction mixture was poured into water (50 mL) and the solidfiltered and dried to afford the desired material as brown oil (3.0 g,84%). NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.35 (3H, t), 1.67 (1H,d), 1.72-1.79 (2H, m), 1.81-1.92 (1H, m), 1.96 (3H, s), 2.19 (2H, ddt),2.79 (3H, s), 2.95 (3H, s), 3.08 (1H, d), 4.23 (1H, s), 4.33 (2H, q),4.45 (1H, s), 4.83 (1H, s), 7.69 (1H, dd), 8.52 (1H, d), 8.85 (1H, s),9.25 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=397.

The preparation of ethyl6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate has been describedpreviously.

Biological Assays

The following assays were used to measure the effects of the compoundsof the present invention: a) ATM cellular potency assay; b) PI3Kcellular potency assay; c) mTOR cellular potency assay; d) ATR cellularpotency assay; e) mouse xenograft model. During the description of theassays, generally:

-   -   i. The following abbreviations have been used:        4NQO=4-Nitroquinoline N-oxide; Ab=Antibody; BSA=Bovine Serum        Albumin; CO₂=Carbon Dioxide; DMEM=Dulbecco's Modified Eagle        Medium; DMSO=Dimethyl Sulphoxide;        EDTA=Ethylenediaminetetraacetic Acid; EGTA=Ethylene Glycol        Tetraacetic Acid; ELISA=Enzyme-linked Immunosorbent Assay;        EMEM=Eagle's Minimal Essential Medium; FBS=Foetal Bovine Serum;        h=Hour(s); HRP=Horseradish Peroxidase; i.p.=intraperitoneal;        PBS=Phosphate buffered saline; PBST=Phosphate buffered        saline/Tween; TRIS=Tris(Hydroxymethyl)aminomethane; MTS reagent:        [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,        inner salt, and an electron coupling reagent (phenazine        methosulfate) PMS; s.c. sub-cutaneously.    -   ii. IC₅₀ values were calculated using a smart fitting model in        Genedata. The IC₅₀ value was the concentration of test compound        that inhibited 50% of biological activity.

Assay a): ATM Cellular Potency Rationale:

Cellular irradiation induces DNA double strand breaks and rapidintermolecular autophosphorylation of serine 1981 that causes dimerdissociation and initiates cellular ATM kinase activity. Most ATMmolecules in the cell are rapidly phosphorylated on this site afterdoses of radiation as low as 0.5 Gy, and binding of a phosphospecificantibody is detectable after the introduction of only a few DNAdouble-strand breaks in the cell.

The rationale of the pATM assay is to identify inhibitors of ATM incells. HT29 cells are incubated with test compounds for lhr prior toX-ray-irradiation. 1 h later the cells are fixed and stained for pATM(Ser1981). The fluorescence is read on the arrayscan imaging platform.

Method Details:

HT29 cells (ECACC #85061109) were seeded into 384 well assay plates(Costar #3712) at a density of 3500 cells/well in 40 μl EMEM mediumcontaining 1% L glutamine and 10% FBS and allowed to adhere overnight.The following morning compounds of Formula (I) in 100% DMSO were addedto assay plates by acoustic dispensing. After 1 h incubation at 37° C.and 5% CO₂, plates (up to 6 at a time) were irradiated using the X-RAD320 instrument (PXi) with equivalent to ˜600 cGy. Plates were returnedto the incubator for a further 1 h. Then cells were fixed by adding 20μl of 3.7% formaldehyde in PBS solution and incubating for 20 minutes atr.t. before being washed with 50 μl/well PBS, using a Biotek EL405 platewasher. Then 20 μl of 0.1% Triton X100 in PBS was added and incubatedfor 20 minutes at r.t., to permeabalise cells. Then the plates werewashed once with 50 μl/well PBS, using a Biotek EL405 plate washer.

Phospho-ATM Ser1981 antibody (Millipore #MAB3806) was diluted 10000 foldin PBS containing 0.05% polysorbate/Tween and 3% BSA and 20 μl was addedto each well and incubated over night at r.t. The next morning plateswere washed three times with 50 μl/well PBS, using a Biotek EL405 platewasher, and then 20 μl of secondary Ab solution, containing 500 folddiluted Alexa Fluor® 488 Goat anti-rabbit IgG (Life Technologies,A11001) and 0.002 mg/ml Hoeschst dye (Life technologies #H-3570), in PBScontaining 0.05% polysorbate/Tween and 3% BSA, was added. After 1 hincubation at r.t., the plates were washed three times with 50 μl/wellPBS, using a Biotek EL405 plate washer, and plates were sealed and keptin PBS at 4° C. until read. Plates were read using an ArrayScan VTIinstrument, using an XF53 filter with 10× objective. A two laser set upwas used to analyse nuclear staining with Hoeschst (405 nm) andsecondary antibody staining of pSer1981 (488 nm).

Assay b): ATR Cellular Potency Rationale:

ATR is a PI 3-kinase-related kinase which phosphorylates multiplesubstrates on serine or threonine residues in response to DNA damage orreplication blocks. Chk1, a downstream protein kinase of ATR, plays akey role in DNA damage checkpoint control. Activation of Chk1 involvesphosphorylation of Ser317 and Ser345 (the latter regarded as thepreferential target for phosphorylation/activation by ATR). This was acell based assay to measure inhibition of ATR kinase, by measuring adecrease in phosphorylation of Chk1 (Ser 345) in HT29 cells, followingtreatment with compound of Formula (I) and the UV mimetic 4NQO (Sigma#N8141).

Method Details:

HT29 cells (ECACC #85061109) were seeded into 384 well assay plates(Costar #3712) at a density of 6000 cells/well in 40 μl EMEM mediumcontaining 1% L glutamine and 10% FBS and allowed to adhere overnight.The following morning compound of Formula (I) in 100% DMSO was added toassay plates by acoustic dispensing. After 1 h incubation at 37° C. and5% CO₂, 40 nl of 3 mM 4NQO in 100% DMSO was added to all wells byacoustic dispensing, except minimum control wells which were leftuntreated with 4NQO to generate a null response control. Plates werereturned to the incubator for a further 1 h. Then cells were fixed byadding 20 μl of 3.7% formaldehyde in PBS solution and incubating for 20mins at r.t. Then 20 μl of 0.1% Triton X100 in PBS was added andincubated for 10 minutes at r.t., to permeabalise cells. Then the plateswere washed once with 50 μl/well PBS, using a Biotek EL405 plate washer.

Phospho-Chk1 Ser 345 antibody (Cell Signalling Technology #2348) wasdiluted 150 fold in PBS containing 0.05% polysorbate/Tween and 15 μl wasadded to each well and incubated over night at r.t. The next morningplates were washed three times with 50 μl/well PBS, using a Biotek EL405plate washer, and then 20 μl of secondary Ab solution, containing 500fold diluted Alexa Fluor 488 Goat anti-rabbit IgG (Molecular Probes#A-11008) and 0.002 mg/ml Hoeschst dye (Molecular Probes #H-3570), inPBST, was added. After 2 h incubation at r.t., the plates were washedthree times with 50 μl/well PBS, using a Biotek EL405 plate washer, andplates were then sealed with black plate seals until read. Plates wereread using an ArrayScan VTI instrument, using an XF53 filter with 10×objective. A two laser set up was used to analyse nuclear staining withHoeschst (405 nm) and secondary antibody staining of pChk1 (488 nm).

Assay c): PI3K Cellular Potency Rationale:

This assay was used to measure PI3K-α inhibition in cells. PDK1 wasidentified as the upstream activation loop kinase of protein kinase B(Akt1), which is essential for the activation of PKB. Activation of thelipid kinase phosphoinositide 3 kinase (PI3K) is critical for theactivation of PKB by PDK1.

Following ligand stimulation of receptor tyrosine kinases, PI3K isactivated, which converts PIP2 to PIPS, which is bound by the PH domainof PDK1 resulting in recruitment of PDK1 to the plasma membrane where itphosphorylates AKT at Thr308 in the activation loop.

The aim of this cell-based mode of action assay is to identify compoundsthat inhibit PDK activity or recruitment of PDK1 to membrane byinhibiting PI3K activity. Phosphorylation of phospho-Akt (T308) inBT474c cells following treatment with compounds for 2 h is a directmeasure of PDK1 and indirect measure of PI3K activity.

Method Details:

BT474 cells (human breast ductal carcinoma, ATCC HTB-20) were seededinto black 384 well plates (Costar, #3712) at a density of 5600cells/well in DMEM containing 10% FBS and 1% glutamine and allowed toadhere overnight.

The following morning compounds in 100% DMSO were added to assay platesby acoustic dispensing. After a 2 h incubation at 37° C. and 5% CO₂, themedium was aspirated and the cells were lysed with a buffer containing25 mM Tris, 3 mM EDTA, 3 mM EGTA, 50 mM sodium fluoride, 2 mM Sodiumorthovanadate, 0.27M sucrose, 10 mM β-glycerophosphate, 5 mM sodiumpyrophosphate, 0.5% Triton X-100 and complete protease inhibitorcocktail tablets (Roche #04 693 116 001, used 1 tab per 50 ml lysisbuffer).

After 20 minutes, the cell lysates were transferred into ELISA plates(Greiner #781077) which had been pre-coated with an anti total-AKTantibody in PBS buffer and non-specific binding was blocked with 1% BSAin PBS containing 0.05% Tween 20. Plates were incubated over night at 4°C. The next day the plates were washed with PBS buffer containing 0.05%Tween 20 and further incubated with a mouse monoclonal anti-phospho AKTT308 for 2 h. Plates were washed again as above before addition of ahorse anti-mouse-HRP conjugated secondary antibody. Following a 2 hincubation at r.t., plates were washed and QuantaBlu substrate workingsolution (Thermo Scientific #15169, prepared according to provider'sinstructions) was added to each well. The developed fluorescent productwas stopped after 60 minutes by addition of Stop solution to the wells.Plates were read using a Tecan S afire plate reader using 325 nmexcitation and 420 nm emission wavelengths respectively. Except wherespecified, reagents contained in the Path Scan Phospho AKT (Thr308)sandwich ELISA kit from Cell Signalling (#7144) were used in this ELISAassay.

Assay d): mTOR Cellular Potency

Rationale:

This assay was used to measure mTOR inhibition in cells. The aim of thephospho-AKT cell based mechanism of action assay using the AcumenExplorer is to identify inhibitors of either PI3Kα or mTOR-Rictor(Rapamycin insensitive companion of mTOR). This is measured by anydecrease in the phosphorylation of the Akt protein at Ser473 (AKT liesdownstream of PI3Kα in the signal transduction pathway) in theMDA-MB-468 cells following treatment with compound.

Method Details:

MDA-MB-468 cells (human breast adenocarcinoma #ATCC HTB 132) were seededat 1500 cells/well in 40 μl of DMEM containing 10% FBS and 1% glutamineinto Greiner 384 well black flat-bottomed plates. Cell plates wereincubated for 18 h in a 37° C. incubator before dosing with compounds offormula (I) in 100% DMSO using acoustic dispensing. Compounds were dosedin a 12 point concentration range into a randomised plate map. Controlwells were generated either by dosing of 100% DMSO (max signal) oraddition of a reference compound (a PI3K-β inhibitor) that completelyeliminated the pAKT signal (min control). Plates were incubated at 37°C. for 2 h, cells were then fixed by the addition of 10 μl of a 3.7%formaldehyde solution. After 30 minutes the plates were washed with PBSusing a Tecan PW384 plate washer. Wells were blocked and cellspermeabilised with the addition of 40 μl of PBS containing 0.5% Tween20and 1% Marvel™ (dried milk powder) and incubated for 60 minutes at r.t.The plates were washed with PBS containing 0.5% (v/v) Tween20 and 20 μlrabbit anti-phospho AKT Ser473 (Cell Signalling Technologies, #3787) insame PBS-Tween+1% Marvel™ was added and incubated overnight at 4° C.

Plates were washed 3 times with PBS+0.05% Tween 20 using a Tecan PW384.20 μl of secondary antibody Alexa Fluor 488 anti-Rabbit (MolecularProbes, #A11008) diluted in PBS+0.05% Tween20 containing 1% Marvel™ wasadded to each well and incubated for 1 h at r.t. Plates were washedthree times as before then 20 μl PBS added to each well and platessealed with a black plate sealer.

The plates were read on an Acumen plate reader as soon as possible,measuring green fluorescence after excitation with 488 nm laser. Usingthis system IC₅₀ values were generated and quality of plates wasdetermined by control wells. Reference compounds were run each time tomonitor assay performance.

Assay e): Mouse Xenograft Model Irinotecan Combination

Male nude mice were transplanted s.c. with SW620 cells (ATCC—CCL-227) todetermine the in-vivo anti-tumour activity of ATM inhibitors. 1×10̂6cells in 50% matrigel (BD Bioscience) were injected s.c. on the leftflank of the animals. Animals were randomised into groups of 10-15 whentumours reached a volume of ˜200-300 mm³ and treatment commenced.Animals received 3 weekly cycles of treatment with compound. Animalswere dosed once weekly with Irinotecan by i.p., and then 24 h postIrinotecan animals received a once daily dose on 3 consecutive days byperoral route with a compound of Formula (I). Tumours were measuredtwice weekly by caliper and volume of tumours calculated usingelliptical formula (π/6×width×width×length). Irinotecan was formulatedin a 7.5% DMSO/92.5% water for injection solution. Compounds of Formula(I) were formulated in a 10% DMSO/90% Captisol (30% w/v) solution.Captisol was sourced from Cydex Pharmaceuticals (Trademarked)β-cyclodextrin suitable for in vivo use and formulations.

Olaparib Combination

Female nude mice were transplanted s.c. with a HBCx-10 patient derivedtumour fragment to determine the in-vivo anti-tumour activity of ATMinhibitors. Human tumour samples of various histological origins wereobtained from patients and established as transplantable xenografts inimmunodeficient mice.

Tumours of the same passage were transplanted subcutaneously onto 5-10mice. When these tumours reached 1000 to 2000 mm³, donor mice weresacrificed by cervical dislocation, tumours were aseptically excised anddissected and cut into fragments measuring approximately 20 mm³ andtransferred in culture medium before grafting. Mice were anaesthetizedand the skin incised at the level of the interscapular region, and a 20mm³ tumour fragment was placed in the subcutaneous tissue

Animals were randomised into groups of 10-12 when tumours reached avolume of 62.5-196 mm³ and treatment commenced. Animals received 8weekly cycles of treatment with compound. Animals were dosed 7 days aweek with Olaparib per orally, and then 1 h prior to Olaparib animalsreceived a once daily dose on 3 consecutive days by per oral route witha compound of Formula (I). Tumours were measured twice weekly by caliperand volume of tumours calculated using formula [length×width²]/2 wasused, where the length and the width are the longest and the shortestdiameters of the tumour, respectively. Olaparib was formulated in a 10%(w/v) DMSO/10% (w/v) HP-b-CD (Kleptose), 80% water for injectionsolution. Compounds of Formula (I) were formulated in a 10% DMSO/90%Captisol (30% w/v) solution. Captisol was sourced from CydexPharmaceuticals (Trademarked) β-cyclodextrin suitable for in vivo useand formulations.

The results of testing Examples 1 and 2 in assay e) are shown in FIGS.3, 4 and 5. “Q7D” Means a once weekly dose. “Q1D” is a once daily dose.

Table 2 shows the results of testing the Examples in assays a) b) c) andd). Where multiple repeat tests were carried out on a given Example, theresult reported is the geometric mean.

TABLE 2 Potency Data for Examples 1-71 in Assays a)-d) Assay a) Assay b)Assay c) Assay d) ATM Cell ATR Cell PI3Kα Cell mTOR Cell Example IC₅₀(μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) 1 0.000575 6.16 1.41 0.61 20.000249 >29 1.77 1.17 3 0.00203 >30 22.4 4.93 4 0.00146 >30 6.84 3.46 50.00024 >30 1.08 1.36 6 0.00105 >30 >30 >16.9 7 0.00096 10.8 0.541 0.2668 0.000782 >30 18.1 14 9 0.0038 >30 >29.1 >21.3 10 0.001 >30 10 5.9 110.00114 >29.6 >20.2 9.29 12 0.00103 >25.2 0.769 0.54 13 0.00322 >30 1.520.248 14 0.00105 >30 0.616 1.04 15 0.000447 >30 2.39 2.58 160.000935 >22.8 0.311 0.714 17 0.000329 >30 0.968 1.47 18 0.000765 >302.73 3.78 19 0.00262 >30 >28 13.7 20 0.000365 >30 1.03 0.529 210.000301 >30 0.68 0.797 22 0.000552 >30 0.849 1.37 23 0.000563 >30 >3018.2 24 0.00069 >18.8 7.29 >9.43 25 0.000315 >20.7 1.05 1.19 260.000152 >21.8 0.331 0.36 27 0.000418 >23.3 >29.8 >17.5 280.000176 >22.8 2.03 2.77 29 0.000238 19 1.65 0.605 30 0.00112 19 2.331.57 31 0.00109 >30 >10.9 19.5 32 0.00178 >30 2.94 6.1 33 0.0002 >24.712.4 2.87 34 0.00084 >16.9 0.402 0.505 35 0.000589 17.8 3 0.579 360.00301 >30 >25 10.6 37 0.0012 >29.4 20.7 12.4 38 0.000292 >24.4 0.7292.24 39 0.00133 10.7 0.828 1.27 40 0.000567 1.33 0.184 0.191 41 0.0005553.94 0.267 0.395 42 0.000249 4.37 0.321 0.214 43 0.000592 2.69 0.1670.262 44 0.00107 >19.2 0.56 2.37 45 <0.000534 9.6 0.26 1.19 460.00315 >26 0.794 47 0.000799 >30 >23.5 >30 48 0.00102 >30 >9.4 23 490.00134 >30 2.03 3.76 50 0.00144 >30 1.1 4.48 51 0.000722 >30 3.2 5.3852 0.00476 >30 7.2 12.1 54 0.0011 >27.1 >16.7 >29.3 54 0.000715 >22.43.47 8.12 55 0.000493 >16.1 >9.13 3.38 56 0.00302 >30 >26.3 12.4 570.000434 >30 >14.3 5.77 58 0.00031 >28.1 >9.56 7.29 59 0.000233 >19.10.264 0.61 60 0.000765 >24 0.499 1.36 61 0.000554 >30 >16.2 620.000507 >30 63 0.00031 >30 3.28 10.8 64 0.000741 >24.1 >30 12 650.00022 >26.6 1.84 6.34 66 0.000334 7.85 1.49 3.32 67 <0.000052515.2 >2.85 0.996 68 0.000208 >29 0.644 3.18 69 0.000324 >30 >2.77 700.00243 >24.9 >30 >30 71 0.00145 >30 >11.4 15.2

Table 3 shows comparative data for certain Compounds of CN102399218A andCN102372711A in tests a) b) c) and d). Where multiple repeat tests werecarried out on a given Compound, the result reported is the geometricmean.

TABLE 3 Potency Data for Certain Compounds of CN102399218A andCN102372711A in Assays a)-d) Assay a) Assay b) Assay c) Assay d)Reference ATM Cell ATR Cell PI3Ka Cell mTOR Cell Compound IC₅₀ (μM) IC₅₀(μM) IC₅₀ (μM) IC₅₀ (μM) CN102372711A 0.125 0.281 0.188 0.237 Compound 1CN102372711A 0.0112 0.0686 0.102 0.0729 Compound 4 CN102372711A 0.02650.0644 0.153 0.113 Compound 5 CN102399218A 1.76 0.418 4.67 2.31 Compound60 CN102399218A 3.46 1.48 1.73 0.177 Compound 61 CN102399218A 0.1350.0553 0.149 0.0155 Compound 62 CN102399218A 0.216 0.162 0.247 0.287Compound 64 CN102399218A 0.494 0.0129 0.0804 0.0414 Compound 94CN102399218A 0.0741 0.0686 0.0131 0.0469 Compound 114

1-15. (canceled)
 16. A method for treating cancer in a warm-bloodedanimal in need of such treatment, which comprises administering to saidwarm-blooded animal a therapeutically effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof,

where: Q is a cyclobutyl or cyclopentyl ring, each of which isoptionally substituted by one hydroxy or methoxy group, or Q is anoxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is optionallysubstituted by one methyl group; R¹ is methyl; R² is hydrogen or methyl;or R¹ and R² together form an azetidinyl, pyrrolidinyl or piperidinylring; R³ is hydrogen or fluoro; R⁴ is hydrogen or methyl; and R⁵ ishydrogen or fluoro.
 17. The method according to claim 16, wherein saidcancer is selected form the group consisting of gastric cancer, diffuselarge B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloidleukaemia, head and neck squamous cell carcinoma, hepatocellularcarcinoma, small cell lung cancer and non-small cell lung cancer. 18.The method according to claim 16, where Q is cyclobutyl,1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl, oxan-3-yl,oxan-4-yl or 4-methyloxan-4-yl.
 19. The method according to claim 16,where Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl oroxan-4-yl.
 20. The method according to claim 16, where R¹ is methyl andR² is hydrogen or methyl.
 21. The method according to claim 16, where R³and R⁵ are both hydrogen.
 22. The method according to claim 16, where R⁴is methyl.
 23. The method according to claim 16 where: Q is1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or4-methyloxan-4-yl; R¹ is methyl; R² is hydrogen or methyl; or R¹ and R²together form an azetidinyl, pyrrolidinyl or piperidinyl ring; R³ ishydrogen or fluoro; R⁴ is hydrogen or methyl; and R⁵ is hydrogen orfluoro.
 24. The method according to claim 16, wherein the compound ofFormula (I) is8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.25. The method according to claim 16, wherein the compound of Formula(I) is a pharmaceutically acceptable salt of8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.26. The method according to claim 16, where the compound of Formula (I),or a pharmaceutically acceptable salt thereof, is administered incombination with radiotherapy.
 27. The method according to claim 16,where the compound of Formula (I), or a pharmaceutically acceptable saltthereof, is administered in combination with at least one additionalanti-tumour substance selected from the group consisting of cisplatin,oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin,pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide,mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide,carmustine, melphalan, bleomycin, olaparib, MEDI4736, AZD1775 andAZD6738.
 28. A compound of Formula (IV), or a salt thereof,

where: Q is a cyclobutyl or cyclopentyl ring, each of which isoptionally substituted by one hydroxy or methoxy group, or Q is anoxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is optionallysubstituted by one methyl group; R⁴ is hydrogen or methyl; R⁵ ishydrogen or fluoro; and X¹ is a leaving group.
 29. The compound ofFormula (IV), or a salt thereof as claimed in claim 28, wherein X¹ is aniodine, bromine, or chlorine atom or a triflate group.
 30. The compoundof Formula (IV), or a salt thereof as claimed in claim 28, where thecompound is 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.